List of phenyltropanes
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Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function.[a] These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's and Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.[2]) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article)[b] Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.
Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.[5]
Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.[c] The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.[d]
Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.
Structure | Short Name i.e. Trivial IUPAC (non-systematic) Name (Singh's #) | R (para-substitution) of benzene | DA [3H]WIN 35428 IC50 nM (Ki nM) | 5HT [3H]paroxetine IC50 nM (Ki nM) | NE [3H]nisoxetine IC50 nM (Ki nM) | selectivity 5-HTT/DAT | selectivity NET/DAT |
---|---|---|---|---|---|---|---|
cocaine (benzoyloxytropane) | H | 102 ± 12 241 ± 18ɑ | 1045 ± 89 112 ± 2b | 3298 ± 293 160 ± 15c | 10.2 0.5d | 32.3 0.7e | |
(para-hydrogen)phenyltropane WIN 35,065-2 (β-CPT[e]) Troparil 11a | H | 23 ± 5.0 49.8 ± 2.2ɑ | 1962 ± 61 173 ± 13b | 920 ± 73 37.2 ± 5.2c | 85.3 3.5d | 40.0 0.7e | |
para-fluorophenyltropane WIN 35,428 (β-CFT[f]) 11b | F | 14 (15.7 ± 1.4) 22.9 ± 0.4ɑ | 156 (810 ± 59) 100 ± 13b | 85 (835 ± 45) 38.6 ± 9.9c | 51.6 4.4d | 53.2 1.7e | |
para-nitrophenyltropane 11k | NO2 | 10.1 ± 0.10 | ? | ? | ? | ? | |
para-aminophenyltropane RTI-29[6] 11j | NH2 | 9.8 24.8 ± 1.3g | 5110 | 151 | 521.4 | 15.4 | |
para-chlorophenyltropane RTI-31 11c | Cl | 1.12 ± 0.06 3.68 ± 0.09ɑ | 44.5 ± 1.3 5.00 ± 0.05b | 37 ± 2.1 5.86 ± 0.67c | 39.7 1.3d | 33.0 1.7e | |
para-methylphenyltropane RTI-32 Tolpane 11f | Me | 1.71 ± 0.30 7.02 ± 0.30ɑ | 240 ± 27 19.38 ± 0.65b | 60 ± 0.53e 8.42 ± 1.53c | 140 2.8d | 35.1 1.2e | |
para-bromophenyltropane RTI-51 Bromopane 11d | Br | 1.81 (1.69) ± 0.30 | 10.6 ± 0.24 | 37.4 ± 5.2 | 5.8 | 20.7 | |
para-iodophenyltropane RTI-55 (β-CIT) Iometopane 11e | I | 1.26 ± 0.04 1.96 ± 0.09ɑ | 4.21 ± 0.3 1.74 ± 0.23b | 36 ± 2.7 7.51 ± 0.82c | 3.3 0.9d | 28.6 3.8e | |
para-hydroxyphenyltropane 11h | OH | 12.1 ± 0.86 | — | — | — | — | |
para-methoxyphenyltropane 11i | OCH3 | 8.14 ± 1.3 | — | — | — | — | |
para-azidophenyltropane 11l | N3 | 2.12 ± 0.13 | — | — | — | — | |
para-trifluoromethylphenyltropane 11m | CF3 | 13.1 ± 2.2 | — | — | — | — | |
para-acetylaminophenyltropane 11n | NHCOCH3 | 64.2 ± 2.6 | — | — | — | — | |
para-propionylaminophenyltropane 11o | NHCOC2H5 | 121 ± 2.7 | — | — | — | — | |
para-ethoxycarbonylaminophenyltropane 11p | NHCO2C3H5 | 316 ± 48 | — | — | — | — | |
para-trimethylstannylphenyltropane 11q | Sn(CH3)3 | 144 ± 37 | — | — | — | — | |
para-ethylphenyltropane RTI-83 11g | Et | 55 ± 2.1 | 28.4 ± 3.8 (2.58 ± 3.5) | 4030 (3910) ± 381 (2360 ± 230) | 0.5 | 73.3 | |
para-n-propylphenyltropane RTI-282i 11r | n-C3H7 | 68.5 ± 7.1 | 70.4 ± 4.1 | 3920 ± 130 | 1.0 | 57.2 | |
para-isopropylphenyltropane 11s | CH(CH3)2 | 597 ± 52 | 191 ± 9.5 | 75000 ± 5820 | 0.3 | 126 | |
para-vinylphenyltropane RTI-359 11t | CH-CH2 | 1.24 ± 0.2 | 9.5 ± 0.8 | 78 ± 4.1 | 7.7 | 62.9 | |
para-methylethenylphenyltropane RTI-283j 11u | C(=CH2)CH3 | 14.4 ± 0.3 | 3.13 ± 0.16 | 1330 ± 333 | 0.2 | 92.4 | |
para-trans-propenylphenyltropane RTI-296i 11v | trans-CH=CHCH3 | 5.29 ± 0.53 | 11.4 ± 0.28 | 1590 ± 93 | 2.1 | 300 | |
para-allylphenyltropane 11x | CH2CH=CH2 | 32.8 ± 3.1 | 28.4 ± 2.4 | 2480 ± 229 | 0.9 | 75.6 | |
para-ethynylphenyltropane RTI-360 11y | C≡CH | 1.2 ± 0.1 | 4.4 ± 0.4 | 83.2 ± 2.8 | 3.7 | 69.3 | |
para-propynylphenyltropane RTI-281i 11z | C≡CCH3 | 2.37 ± 0.2 | 15.7 ± 1.5 | 820 ± 46 | 6.6 | 346 | |
para-cis-propenylphenyltropane RTI-304 11w | cis-CH=CHCH3 | 15 ± 1.2 | 7.1 ± 0.71 | 2,800k ± 300 | 0.5 | 186.6k | |
para-(Z)-phenylethenylphenyltropane | cis-CH=CHPh | 11.7 ± 1.12 | — | — | — | — | |
para-benzylphenyltropane | -CH2-Ph | 526 ± 65 | 7,240 ± 390 (658 ± 35) | 6670 ± 377 (606 ± 277) | 13.7 | 12.6 | |
para-phenylethenylphenyltropane | CH2 ║ -C-Ph | 474 ± 133 | 2,710 ± 800 (246 ± 73) | 7,060 ± 1,760 (4,260 ± 1,060) | 5.7 | 14.8 | |
para-phenylethylphenyltropanel | -(CH2)2-Ph | 5.14 ± 0.63 | 234 ± 26 (21.3 ± 2.4) | 10.8 ± 0.3 (6.50 ± 0.20) | 45.5 | 2.1 | |
para-(E)-phenylethenylphenyltropanel RTI-436 | trans–CH=CHPh | 3.09 ± 0.75 | 335 ± 150 (30.5 ± 13.6) | 1960 ± 383 (1180 ± 231) | 108.4 | 634.3 | |
para-phenylpropylphenyltropanel | -(CH2)3-Ph | 351 ± 52 | 1,243 ± 381 (113 ± 35) | 14,200 ± 1,800 (8,500 ± 1,100) | 3.5 | 40.4 | |
para-phenylpropenylphenyltropanel | -CH=CH-CH2-Ph | 15.8 ± 1.31 | 781 ± 258 (71 ± 24) | 1,250 ± 100 (759 ± 60) | 49.4 | 79.1 | |
para-phenylbutylphenyltropanel | -(CH2)4-Ph | 228 ± 21 | 4,824 ± 170 (439 ± 16) | 2,310 ± 293 (1,390 ± 177) | 21.1 | 10.1 | |
para-phenylethynylphenyltropanel RTI-298[7] | –≡–Ph | 3.7 ± 0.16 | 46.8 ± 5.8 (4.3 ± 0.53) | 347 ± 25 (209 ± 15) | 12.6 | 93.7 | |
para-phenylpropynylphenyltropanel[8] | –C≡C-CH2Ph | 1.82 ± 0.42 | 13.1 ± 1.7 (1.19 ± 0.42) | 27.4 ± 2.6 (16.5 ± 1.6) | 7.1 | 15 | |
para-phenylbutynylphenyltropanel RTI-430 | –C≡C(CH2)2Ph | 6.28 ± 1.25 | 2180 ± 345 (198 ± 31) | 1470 ± 109 (885 ± 66) | 347.1 | 234 | |
para-phenylpentynylphenyltropanel | –C≡C-(CH2)3-Ph | 300 ± 37 | 1,340 ± 232 (122 ± 21) | 4,450 ± 637 (2,680 ± 384) | 4.46 | 14.8 | |
para-trimethylsilylethynylphenyltropane[3] | — | — | — | — | — | — | |
para-hydroxypropynylphenyltropane[3] | — | — | — | — | — | — | |
para-hydroxyhexynylphenyltropanel | –C≡C-(CH2)4OH | 57 ± 4 | 828 ± 29 (75 ± 2.6) | 9,500 ± 812 (5,720 ± 489) | 14.5 | 166.6 | |
para-(thiophen-3-yl)phenyltropane Tamagnan[4] | p-thiophene | 12 | 0.017 | 189 | 0.001416 | 15.7 | |
para-biphenyltropane 11aa | Ph | 10.3 ± 2.6f 29.4 ± 3.8ɑ 15.6 ± 0.6 | 95.8 ± 36 (8.7 ± 3.3) | 1,480 ± 269 (892 ± 162) | 6.1 | 94.8 | |
3β-2-naphthyltropane RTI-318 11bb | 3β-2-naphthyl | 0.51 ± 0.03 3.32 ± 0.08f 3.53 ± 0.09ɑ | 0.80 ± 0.06 (0.07 ± 0.1) | 21.1 ± 1.0 (12.7 ± 0.60) | 1.5 | 41.3 | |
para-bimethoxyphenyltropane 15 | OCH2OCH3h | — | — | — | — | — |
|
|
|
(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes
[edit]Compound structure | Alphanumeric code (name) | para-substitution | N8 | SERT | DAT | NET | Selectivity SERT versus DAT | Selectivity SERT versus NET |
---|---|---|---|---|---|---|---|---|
1 (cocaine) | (—)-Cocaine | CH3 | 1050 | 89 | 3320 | 0.08 | 3.2 | |
2 (β-CIT), (Iometopane) | Iodo | CH3 | 0.46 ± 0.06 | 0.96 ± 0.15 | 2.80 ± 0.40 | 2.1 | 6.1 | |
(R,S-Citalopram) | — | — | 1.60 | 16,540 | 6,190 | 10,338 | 3,869 | |
4a | 2-Thiophene | CH3 | 0.15 ± 0.015 | 52 ± 12.8 | 158 ± 12 | 346 | 1,053 | |
4b (Tamagnan) | 3-Thiophene | CH3 | 0.017 ± 0.004 | 12.1 ± 3 | 189 ± 82 | 710 | 11,118 | |
4c | 2-(5-Br)-Thiophene | CH3 | 0.38 ± 0.008 | 6.43 ± 0.9 | 324 ± 19 | 17 | 853 | |
4d | 2-(5-Cl)-Thiophene | CH3 | 0.64 ± 0.04 | 4.42 ± 1.64 | 311 ± 25 | 6.9 | 486 | |
4e | 2-(5-I)-Thiophene | CH3 | 4.56 ± 0.84 | 22.1 ± 3.2 | 1,137 ± 123 | 4.9 | 249 | |
4f | 2-(5-NH2)-Thiophene | CH3 | 64.7 ± 3.7 | >10,000 | >30,000 | >155 | >464 | |
4g | 2-(4,5-NO2)-Thiophene | CH3 | 5,000 | >30,000 | >10,000 | >6.0 | >2.0 | |
4h | 3-(4-Br)-Thiophene | CH3 | 4.02 ± 0.34 | 183 ± 69 | >10,000 | 46 | >2,488 | |
5a | 2-Thiophene | H | 0.11 ± 0.006 | 12.2 ± 0.9 | 75.3 ± 9.6 | 111 | 685 | |
5b | 3-Thiophene | H | 0.23 ± 0.02 | 6.4 ± 0.27 | 39 ± 0.8 | 28 | 170 |
(3′,4′-Disubstituted phenyl)-tropanes
[edit]Compound (+ S. Singh's name) | X (4′-para) | Y (3′-meta) | 2 Position | config | 8 | DA | 5-HT | NE |
---|---|---|---|---|---|---|---|---|
RTI-318 11bb | β-naphthyl | CO2Me | β,β | NMe | 0.5 | 0.81 | 20 | |
Dichloropane (RTI-111ɑ)[10] 17c | Cl | Cl | CO2Me | β,β | NMe | 0.79 | 3.13 | 18.0 |
RTI-88 [recheck] 17e | NH2 | I | CO2Me | β,β | NMe | 1.35 | 1329c | 320c |
RTI-97 17d | NH2 | Br | CO2Me | β,β | NMe | 3.91 | 181 | 282 |
RTI-112b 17b | Cl | Me | CO2Me | β,β | NMe | 0.82 | 10.5 | 36.2 |
RTI-96 17a | F | Me | CO2Me | β,β | NMe | 2.95 | 76 | 520 |
RTI-295 | Et | I | CO2Me | β,β | NMe | 21.3 | 2.96 | 1349 |
RTI-353 (EINT) | Et | I | CO2Me | β,β | NH | 331 | 0.69 | 148 |
RTI-279 | Me | I | CO2Me | β,β | NH | 5.98 | 1.06 | 74.3 |
RTI-280 | Me | I | CO2Me | β,β | NMe | 3.12 | 6.81 | 484 |
Meltzer[11] | catechol | CO2Me | β,β | NMe | >100 | ? | ? | |
Meltzer[11] | OAc | OAc | CO2Me | β,β | NMe | ? | ? | ? |
- ɑas ·HCl (salt)
- bas ·HCl·2 H2O (salt)
- cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT
Compound | Short Name (S. Singh) | R2 | R1 | DA | 5HT | NE | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|
meta-fluorophenyltropane 16a | F | H | 23 ± 7.8 | - | - | - | - | |
meta-chlorophenyltropane 16b | Cl | H | 10.6 ± 1.8 | - | - | - | - | |
meta-bromophenyltropane 16c | Br | H | 7.93 ± 0.08ɑ | - | - | - | - | |
meta-iodophenyltropane 16d | I | H | 26.1 ± 1.7 | - | - | - | - | |
meta-tributylstannylphenyltropane 16e | SnBu3 | H | 1100 ± 170 | - | - | - | - | |
meta-ethynylphenyltropane[3] | C≡CH | H | - | - | - | - | - | |
meta-methyl-para-fluorophenyltropane RTI-96 17a | CH3 | F | 2.95 ± 0.58 | - | - | - | - | |
meta-methyl-para-chlorophenyltropane RTI-112c 17b | CH3 | Cl | 0.81 ± 0.05 | 10.5 ± 0.05 | 36.2 ± 1.0 | 13.0 | 44.7 | |
meta-para-dichlorophenyltropane RTI-111b[10] Dichloropane 17c | Cl | Cl | 0.79 ± 0.08b | 3.13 ± 0.36b | 18.0 ± 0.8 17.96 ± 0.85'b'd | 4.0b | 22.8b | |
meta-bromo-para-aminophenyltropane RTI-97 17d | Br | NH2 | 3.91 ± 0.59 | 181 | 282 | 46.2 | 72.1 | |
meta-iodo-para-aminophenyltropane RTI-88 17e | I | NH2 | 1.35 ± 0.11 | 120 ± 4 | 1329 ± 124 | 88.9 | 984 | |
meta-iodo-para-azidophenyltropane 17f | I | N3 | 4.93 ± 0.32 | - | - | - | - |
- ɑIC50 determined in Cynomolgous monkey caudate-putamen
- bas ·HCl (salt)
- cas ·HCl·2 H2O (salt)
- dNEN
Structure | Compound | R | X | n | Inhibition of [3H]WIN 35,428 @ DAT IC50 (nM) | Inhibition of [3H]Paroxetine @ 5-HTT Ki (nM) | Inhibition of [3H]Nisoxetine @ NET Ki (nM) | NET/DAT (uptake ratio) | NET/5-HTT (uptake ratio) |
---|---|---|---|---|---|---|---|---|---|
Cocaine | Des-thio/sulfinyl/sulfonyl H | H | Desmethyl 0 | 89.1 | 95 | 1990 | 22 | 21 | |
para-methoxyphenyltropane Singh: 11i | Des-thio/sulfinyl/sulfonyl OCH3 | H | 0 | 6.5 ± 1.3 | 4.3 ± 0.5 | 1110 ± 64 | 171 | 258 | |
7a | CH3 | H | 0 | 9 ± 3 | 0.7 ± 0.2 | 220 ± 10 | 24 | 314 | |
7b | C2H5 | H | 0 | 232 ± 34 | 4.5 ± 0.5 | 1170 ± 300 | 5 | 260 | |
7c | CH(CH3)2 | H | 0 | 16 ± 2 | 23 ± 2 | 129 ± 2 | 8 | 7 | |
7d | CF3 | H | 0 | 200 ± 70 | 8 ± 2 | 1900 ± 300 | 10 | 238 | |
7e | CH3 | Br | 0 | 10.1 ± 1 | 0.6 ± 0.2 | 121 ± 12 | 12 | 202 | |
7f | CH3 | Br | 1 | 76 ± 18 | 3.2 ± 0.4 | 690 ± 80 | 9 | 216 | |
7g | CH3 | H | 1 | 91 ± 16 | 4.3 ± 0.6 | 515 ± 60 | 6 | 120 | |
7h | CH3 | H | 2 | >10,000 | 208 ± 45 | >10,000 | 1 | 48 |
(2′,4′-Disubstituted phenyl)-tropanes
[edit]Compound structure | Trivial IUPAC (non-systematic) Name | R2 ortho | R1 para | DA | 5HT | NE | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|
ortho,para-dinitrophenyltropane[13] | NO2 | NO2 | - | - | - | - | - |
(3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes
[edit]Structure | Short Name (All compounds tested as HCl salts) | R2 3′-(meta) | R3 5′-(di-meta) | OR1 4′-(para) | DAT IC50 [3H](compound #)12 | 5-HTT Ki [3H]Paroxetine | NET Ki [3H]Nisoxetine | Selectivity NET/DAT Ratio Ki/IC50 | Selectivity NET/5-HTT Ratio Ki/Ki |
---|---|---|---|---|---|---|---|---|---|
Cocaine | - | - | - | 89.1 | 95 | 1990 | 22 | 21 | |
6 RTI-112 | - | - | - | 0.82 ± 0.05 | 0.95 ± 0.04 | 21.8 ± 0.6 | 27 | 23 | |
7a 11i | H | H | CH3 | 6.5 ± 1.3 | 4.3 ± 0.5 | 1110 ± 64 | 171 | 258 | |
7b | H | H | C2H5 | 92 ± 8 | 1.7 ± 0.4 | 1690 ± 50 | 18 | 994 | |
7c | F | H | CH3 | 16 ± 1 | 4.8 ± 0.5 | 270 ± 50 | 17 | 56 | |
7d | Br | H | CH3 | 47 ± 15 | 3.1 ± 0.1 | 160 ± 20 | 3 | 52 | |
7f | Br | Br | CH3 | 92 ± 22 | 2.9 ± 0.1 | 4100 ± 400ɑ | 45 | 1413 | |
7e | I | H | CH3 | 170 ± 60 | 3.5 ± 0.4 | 180 ± 20 | 1 | 51 | |
7g | I | I | CH3 | 1300 ± 200 | 7.5 ± 0.8 | 180 ± 20 | 4 | 667 |
ɑN=2
(2′,4′,5′-Trisubstituted phenyl)-tropanes
[edit]Structure | Short Name | R1 2′-(ortho) | R2 4′-(para) | R3 5′-(meta) | DAT | 5-HTT | NET | Selectivity NET/DAT Ratio | Selectivity NET/5-HTT Ratio |
---|---|---|---|---|---|---|---|---|---|
para-ethyl-ortho, meta-diiodophenyltropane[3] | iodo | ethyl | iodo | - | - | - | - | - |
2-Carbmethoxy modified (replaced/substituted)
[edit]General 2-carbmethoxy modifications
[edit]2β-substitutions of p-methoxy-phenyltropanes
[edit]Structure | Short Name (All compounds tested as HCl salts) | CO2R (2β-substituted) (compound 9 is 2β=R) | DAT IC50 [3H](compound #)12 | 5-HTT Ki [3H]Paroxetine | NET Ki [3H]Nisoxetine | Selectivity NET/DAT Ratio Ki/IC50 | Selectivity NET/5-HTT Ratio Ki/Ki |
---|---|---|---|---|---|---|---|
7a 11i | CH3 | 6.5 ± 1.3 | 4.3 ± 0.5 | 1110 ± 64 | 171 | 258 | |
8a | (CH3)2CH | 14 ± 3 | 135 ± 35 | 2010 ± 200 | 144 | 15 | |
8b | cyclopropane | 6.0 ± 2 | 29 ± 3 | 1230 ± 140 | 205 | 42 | |
8c | cyclobutane | 13 ± 3 | 100 ± 8 | >3000 | 231 | 30 | |
8d | O2N...1,4-xylene...(CH2)2 | 42 ± 8 | 2.9 ± 0.2 | 330 ± 20 | 8 | 114 | |
8e | H2N...1,4-xylene...(CH2)2 | 7.0 ± 2 | 8.3 ± 0.4 | 2200 ± 300ɑ | 314 | 265 | |
8f | CH3CONH...1,4-xylene...(CH2)2 | 6.0 ± 1 | 5.5 ± 0.5 | 1460 ± 30 | 243 | 265 | |
8g | H2N...2-bromo-1,4-dimethylbenzene...(CH2)2 | 3.3 ± 1.4 | 4.1 ± 0.6 | 1850 ± 90 | 561 | 451 | |
8h | H2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)2 | 15 ± 6 | 2.0 ± 0.4 | 2710 ± 250ɑ | 181 | 1360 | |
8i | H2N...2-iodo-1,4-dimethylbenzene...(CH2)2 | 2.5 ± 0.7 | 3.5 ± 1 | 2040 ± 300ɑ | 816 | 583 | |
8j | H2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2 | 102 ± 15 | 1.0 ± 0.1 | 2600 ± 200ɑ | 25 | 2600 | |
9 | 3-(4-methylphenyl)-1,2-oxazole | 18 ± 6 | 860 ± 170 | >3000 | 167 | 3 |
ɑN=2
2β-carboxy side-chained (p-chloro/iodo/methyl) phenyltropanes
[edit]Compound | Short Name (S. Singh) | R | X | IC50 (nM) DAT [3H]WIN 35428 | IC50 (nM) 5-HTT [3H]paroxetine | IC50 (nM) NET [3H]nisoxetine | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|
23a | CH(CH3)2 | H | 85.1 ± 2.5 | 23121 ± 3976 | 32047 ± 1491 | 272 | 376 | |
23b | C6H5 | H | 76.7 ± 3.6 | 106149 ± 7256 | 19262 ± 593 | 1384 | 251 | |
24a | CH(CH3)2 | Cl | 1.4 ± 0.13 6.04 ± 0.31ɑ | 1400 ± 7 128 ± 15b | 778 ± 21 250 ± 0.9c | 1000 21.2d | 556 41.4e | |
24b | cyclopropyl | Cl | 0.96 ± 0.10 | 168 ± 1.8 | 235 ± 8.39 | 175 | 245 | |
24c | C6H5 | Cl | 1.99 ± 0.05 5.25 ± 0.76ɑ | 2340 ± 27 390 ± 34b | 2960 ± 220 242 ± 30c | 1176 74.3d | 1.3 41.6e | |
24d | C6H4-4-I | Cl | 32.6 ± 3.9 | 1227 ± 176 | 967.6 ± 26.3 | 37.6 | 29.7 | |
24e | C6H4-3-CH3 | Cl | 9.37 ± 0.52 | 2153 ± 143 | 2744 ± 140 | 230 | 293 | |
24f | C6H4-4-CH3 | Cl | 27.4 ± 1.5 | 1203 ± 42 | 1277 ± 118 | 43.9 | 46.6 | |
24g | C6H4-2-CH3 | Cl | 3.91 ± 0.23 | 3772 ± 384 | 4783 ± 387 | 965 | 1223 | |
24h | C6H4-4-Cl | Cl | 55 ± 2.3 | 16914 ± 1056 | 4883 ± 288 | 307 | 88.8 | |
24i | C6H4-4-OCH3 | Cl | 71 ± 5.6 | 19689 ± 1843 | 1522 ± 94 | 277 | 21.4 | |
24j | (CH2)2C6H4-4-NO2 | Cl | 2.71 ± 0.13 | - | - | - | - | |
24k | (CH)2C6H4-4-NH2 | Cl | 2.16 ± 0.25 | - | - | - | - | |
24l | (CH2)2C6H3-3-I-4-NH2 | Cl | 2.51 ± 0.25 | - | - | - | - | |
24m | (CH2)2C6H3-3-I-4-N3 | Cl | 14.5 ± 0.94 | - | - | - | - | |
24n | (CH2)2C6H4-4-N3 | Cl | 6.17 ± 0.57 | - | - | - | - | |
24o | (CH2)2C6H4-4-NCS | Cl | 5.3 ± 0.6 | - | - | - | - | |
24p | (CH2)2C6H4-4-NHCOCH2Br | Cl | 1.73 ± 0.06 | - | - | - | - | |
25a | CH(CH3)2 | I | 0.43 ± 0.05 2.79 ± 0.13ɑ | 66.8 ± 6.53 12.5 ± 1.0b | 285 ± 7.6 41.2 ± 3.0c | 155 4.5d | 663 14.8e | |
25b | cyclopropyl | I | 0.61 ± 0.08 | 15.5 ± 0.72 | 102 ± 11 | 25.4 | 167 | |
25c | C6H5 | I | 1.51 ± 0.34 6.85 ± 0.93ɑ | 184 ± 22 51.6 ± 6.2b | 3791 ± 149 32.7 ± 4.4c | 122 7.5d | 2510 4.8e | |
26a | CH(CH3)2 | CH3 | 6.45 ± 0.85 15.3 ± 2.08ɑ | 6090 ± 488 917 ± 54b | 1926 ± 38 73.4 ± 11.6c | 944 59.9d | 299 4.8e | |
26b | CH(C2H5)2 | CH3 | 19.1 ± 1 | 4499 ± 557 | 3444 ± 44 | 235 | 180 | |
26c | cyclopropyl | CH3 | 17.8 ± 0.76 | 485 ± 21 | 2628 ± 252 | 27.2 | 148 | |
26d | cyclobutyl | CH3 | 3.74 ± 0.52 | 2019 ± 133 | 4738 ± 322 | 540 | 1267 | |
26e | cyclopentyl | CH3 | 1.68 ± 0.14 | 1066 ± 109 | 644 ± 28 | 634 | 383 | |
26f | C6H5 | CH3 | 3.27 ± 0.06 9.13 ± 0.79ɑ | 24500 ± 1526 1537 ± 101b | 5830 ± 370 277 ± 23c | 7492 168d | 1783 30.3e | |
26g | C6H4-3-CH3 | CH3 | 8.19 ± 0.90 | 5237 ± 453 | 2136 ± 208 | 639 | 261 | |
26h | C6H4-4-CH3 | CH3 | 81.2 ± 16 | 15954 ± 614 | 4096 ± 121 | 196 | 50.4 | |
26i | C6H4-2-CH3 | CH3 | 23.2 ± 0.97 | 11040 ± 504 | 25695 ± 1394 | 476 | 1107 | |
26j | C6H4-4-Cl | CH3 | 117 ± 7.9 | 42761 ± 2399 | 9519 ± 864 | 365 | 81.3 | |
26k | C6H4-4-OCH3 | CH3 | 95.6 ± 8.8 | 82316 ± 7852 | 3151 ± 282 | 861 | 33.0 |
- ɑKi value for displacement of [3H]DA uptake.
- bKi value for displacement of [3H]5-HT uptake.
- cKi value for displacement of [3H]NE uptake.
- d[3H]5-HT uptake to [3H]DA uptake ratio.
- e[3H]NE uptake to [3H]DA uptake ratio.
Carboxyaryl
[edit]Compound | X | 2 Position | config | 8 | DA | 5-HT | NE |
---|---|---|---|---|---|---|---|
RTI-122 | I | -CO2Ph | β,β | NMe | 1.50 | 184 | 3,791 |
RTI-113 | Cl | -CO2Ph | β,β | NMe | 1.98 | 2,336 | 2,955 |
RTI-277 | NO2 | -CO2Ph | β,β | NMe | 5.94 | 2,910 | 5,695 |
RTI-120 [recheck] | Me | -CO2Ph | β,β | NMe | 3.26 | 24,471 | 5,833 |
RTI-116 | Cl | -CO2(p-C6H4I) | β,β | NMe | 33 | 1,227 | 968 |
RTI-203 | Cl | CO2(m-C6H4Me) | β,β | NMe | 9.37 | 2153 | 2744 |
RTI-204 | Cl | -CO2(o-C6H4Me) | β,β | NMe | 3.91 | 3,772 | 4,783 |
RTI-205 | Me | -CO2(m-C6H4Me) | β,β | NMe | 8.19 | 5,237 | 2,137 |
RTI-206 | Cl | -CO2(p-C6H4Me) | β,β | NMe | 27.4 | 1,203 | 1,278 |
2-Phenyl-3-Phenyltropanes
[edit]Compound Structure | Short Name (S. Singh) | Stereochemistry | X (para) | DAT [3H]WIN 35428 IC50 (nM) | DAT [3H]Mazindol Ki (nM) | 5-HTT [3H]Paroxetine IC50 (nM) | [3H]DA uptake Ki (nM) | [3H]5-HT uptake Ki (nM) | Selectivity [3H]5-HT/[3H]DA |
---|---|---|---|---|---|---|---|---|---|
Cocaine | (2β,3β) | (H) | 89 ± 4.8 | 281 | 1050 ± 89 | 423 | 155 | 0.4 | |
67a | 2β,3β | H | 12.6 ± 1.8 | 14.9 | 21000 ± 3320 | 28.9 | 1100 | 38.1 | |
67b | 2β,3α | H | - | 13.8 | - | 11.7 | 753 | 64.3 | |
67c | 2α,3α | H | 690 ± 37 | - | 41300 ± 5300 | - | - | - | |
68 | 2β,3α | F | - | 6.00 | - | 4.58 | 122 | 26.6 | |
69a | 2β,3β | CH3 | 1.96 ± 0.08 | 2.58 | 11000 ± 83 | 2.87 | 73.8 | 25.7 | |
69b | 2β,3α | CH3 | - | 2.87 | - | 4.16 | 287 | 69.0 | |
69c | 2α,3α | CH3 | 429 ± 59 | - | 15800 ± 3740 | - | - | - |
Carboxyalkyl
[edit]Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
---|---|---|---|---|---|---|---|
RTI-77 | Cl | CH2C2(3-iodo-p-anilino) | β,β | NMe | 2.51 | — | 2247 |
RTI-121 IPCIT | I | -CO2Pri | β,β | NMe | 0.43 | 66.8 | 285 |
RTI-153 | I | -CO2Pri | β,β | NH | 1.06 | 3.59 | 132 |
RTI-191 | I | -CO2Prcyc | β,β | NMe | 0.61 | 15.5 | 102 |
RTI-114 | Cl | -CO2Pri | β,β | NMe | 1.40 | 1,404 | 778 |
RTI-278 | NO2 | -CO2Pri | β,β | NMe | 8.14 | 2,147 | 4,095 |
RTI-190 | Cl | -CO2Prcyc | β,β | NMe | 0.96 | 168 | 235 |
RTI-193 | Me | -CO2Prcyc | β,β | NMe | 1.68 | 1,066 | 644 |
RTI-117 | Me | -CO2Pri | β,β | NMe | 6.45 | 6,090 | 1,926 |
RTI-150 | Me | -CO2Bucyc | β,β | NMe | 3.74 | 2,020 | 4,738 |
RTI-127 | Me | -CO2C(H)Et2 | β,β | NMe | 19 | 4500 | 3444 |
RTI-338 | ethyl | -CO2C2Ph | β,β | NMe | 1104 | 7.41 | 3366 |
Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.
Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.
2-Alkyl Esters & Ethers
[edit]Esters (2-Alkyl)
[edit]Structure | Short Name (S. Singh) | 2β=R | Ki (nM) DAT [3H]WIN 35428 | IC50 (nM) [3H]DA uptake | Selectivity uptake/binding |
---|---|---|---|---|---|
59a | CH=CHCO2CH3 | 22 ± 2 | 123 ± 65 | 5.6 | |
59b | CH2CH2CO2CH3 | 23 ± 2 | 166 ± 68 | 7.2 | |
59c | (CH2)2CH=CHCO2CH3 | 20 ± 2 | 203 ± 77 | 10.1 | |
59d | (CH22)4CO2CH3 | 30 ± 2 | 130 ± 7 | 4.3 | |
59e | CH=CHCH2OH | 26 ± 3 | 159 ± 43 | 6.1 | |
59f | CH2CH2CH2OH | 11 ± 1 | 64 ± 32 | 5.8 | |
59g | CH2CH2COC6H5 | 28 ± 2 | 47 ± 15 | 1.7 |
Ethers (2-Alkyl)
[edit]See the N-desmethyl Paroxetine homologues
Molecular Structure | Short Name (S. Singh) | Stereochemistry | DAT [3H]WIN 35428 IC50 (nM) | 5-HTT [3H]Paroxetine IC50 (nM) | NET [3H]Nisoxetine IC50 (nM) | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|
Paroxetine | 623 ± 25 | 0.28 ± 0.02 | 535 ± 15 | 0.0004 | 0.8 | ||
R-60a | 2β,3β | 308 ± 20 | 294 ± 18 | 5300 ± 450 | 0.9 | 17.2 | |
R-60b | 2α,3β | 172 ± 8.8 | 52.9 ± 3.6 | 26600 ± 1200 | 0.3 | 155 | |
R-60c | 2β,3α | 3.01 ± 0.2 | 42.2 ± 16 | 123 ± 9.5 | 14.1 | 40.9 | |
S-60d | 2β,3β | 1050 ± 45 | 88.1 ± 2.8 | 27600 ± 1100 | 0.08 | 26.3 | |
S-60e | 2α,3β | 1500 ± 74 | 447 ± 47 | 2916 ± 1950 | 0.3 | 1.9 | |
S-60f | 2β,3α | 298 ± 17 | 178 ± 13 | 12400 ± 720 | 0.6 | 41.6 |
Carboxamides
[edit]Structure | Code (S. Singh #) | X | 2 Position | config | 8 | DA [3H]WIN 35428 (IC50 nM) | NE [3H]nisoxetine | 5-HT [3H]paroxetine (IC50 nM) | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|---|---|
RTI-106 27b | Cl | CON(H)Me | β,β | NMe | 12.4 ± 1.17 | 1584 ± 62 | 1313 ± 46 | 106 | 128 | |
RTI-118 27a | Cl | CONH2 | β,β | NMe | 11.5 ± 1.6 | 4270 ± 359 | 1621 ± 110 | 141 | 371 | |
RTI-222 29d | Me | morpholinyl | β,β | NMe | 11.7 ± 0.87 | 23601 ± 1156 | >100K | >8547 | 2017 | |
RTI-129 27e | Cl | CONMe2 | β,β | NMe | 1.38 ± 0.1 | 942 ± 48 | 1079 ± 102 | 792 | 683 | |
RTI-146 27d | Cl | CONHCH2OH | β,β | NMe | 2.05 ± 0.23 | 144 ± 3 | 97.8 ± 10 | 47.7 | 70.2 | |
RTI-147 27i | Cl | CON(CH2)4 | β,β | NMe | 1.38 ± 0.03 | 3,950 ± 72 | 12400 ± 1207 | 8985 | 2862 | |
RTI-156 | Cl | CON(CH2)5 | β,β | NMe | 6.61 | 5832 | 3468 | |||
RTI-170 | Cl | CON(H)CH2C≡CH | β,β | NMe | 16.5 | 1839 | 4827 | |||
RTI-172 | Cl | CON(H)NH2 | β,β | NMe | 44.1 | 3914 | 3815 | |||
RTI-174 | Cl | CONHCOMe | β,β | NMe | 158 | >43K | >125K | |||
RTI-182 | Cl | CONHCH2COPh | β,β | NMe | 7.79 | 1722 | 827 | |||
RTI-183✲ 27 g | Cl | CON(OMe)Me | β,β | NMe | 0.85 ± 0.06 | 549 ± 18.5 | 724 ± 94 | 852 | 646 | |
RTI-186 29c | Me | CON(OMe)Me | β,β | NMe | 2.55 ± 0.43 | 422 ± 26 | 3402 ± 353 | 1334 | 165 | |
RTI-198 27h | Cl | CON(CH2)3 | β,β | NMe | 6.57 ± 0.67 | 990 ± 4.8 | 814 ± 57 | 124 | 151 | |
RTI-196 27c | Cl | CONHOMe | β,β | NMe | 10.7 ± 1.25 | 9907 ± 632 | 43700 ± 1960 | 4084 | 926 | |
RTI-201 | Cl | CONHNHCOPh | β,β | NMe | 91.8 | >20K | >48K | |||
RTI-208 27j | Cl | CONO(CH2)3 | β,β | NMe | 1.47 ± 0.13 | 1083 ± 76 | 2470 ± 56 | 1680 | 737 | |
RTI-214 27l | Cl | CON(-CH2CH2-)2O | β,β | NMe | 2.90 ± 0.3 | 8545 ± 206 | 88769 ± 1855 | 30610 | 2946 | |
RTI-215 27f | Cl | CONEt2 | β,β | NMe | 5.48 ± 0.19 | 5532 ± 299 | 9433 ± 770 | 1721 | 1009 | |
RTI-217 | Cl | CONH(m-C6H4OH) | β,β | NMe | 4.78 | >30K | >16K | |||
RTI-218✲ | Cl | CON(Me)OMe | β,β | NMe | 1.19 | 520 | 1911 | |||
RTI-226 27 m | Cl | CONMePh | β,β | NMe | 45.5 ± 3 | 2202 ± 495 | 23610 ± 2128 | 519 | 48.4 | |
RTI-227 | I | CONO(CH2)3 | β,β | NMe | 0.75 | 446 | 230 | |||
RTI-229[16] 28a | I | CON(CH2)4 | β,β | NMe | 0.37 ± 0.04 | 991 ± 21 | 1728 ± 39 | 4670 | 2678 | |
27k | 6.95 ± 1.21 | 1752 ± 202 | 3470 ± 226 | 499 | 252 | |||||
28b | 1.08 ± 0.15 | 103 ± 6.2 | 73.9 ± 8.1 | 68.4 | 95.4 | |||||
28c | 0.75 ± 0.02 | 357 ± 42 | 130 ± 15.8 | 173 | 476 | |||||
29a | 41.8 ± 2.45 | 4398 ± 271 | 6371 ± 374 | 152 | 105 | |||||
29b | 24.7 ± 1.93 | 6222 ± 729 | 33928 ± 2192 | 1374 | 252 |
✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.
Compound | Short Name (S. Singh) | R | X | IC50 (nM) DAT [3H]WIN 35428 | IC50 (nM) 5-HTT [3H]Paroxetine | IC50 (nM) NET [3H]Nisoxetine | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|
29a | NH2 | CH3 | 41.8 ± 2.45 | 6371 ± 374 | 4398 ± 271 | 152 | 105 | |
29b | N(CH2CH3)2 | CH3 | 24.7 ± 1.93 | 33928 ± 2192 | 6222 ± 729 | 1374 | 252 | |
29c RTI-186 | N(OCH3)CH3 | CH3 | 2.55 ± 0.43 | 3402 ± 353 | 422 ± 26 | 1334 | 165 | |
29d RTI-222 | 4-morpholine | CH3 | 11.7 ± 0.87 | >100000 | 23601 ± 1156 | >8547 | 2017 |
Carboxamide linked phenyltropanes dimers
[edit]
Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo.[3]
Heterocycles
[edit]These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize[17] to the energetically more favorable trans configuration. This can happen to cocaine also.
Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.
To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔVmin(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔVmin(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.
In contrast to this trend, it is understood that an increasingly negative ΔVmin is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.[g]
3-Substituted-isoxazol-5-yl
[edit]Code (S.S. #) | X | R | DA | NE | 5HT |
---|---|---|---|---|---|
RTI-165 | Cl | 3-methylisoxazol-5-yl | 0.59 | 181 | 572 |
RTI-171 | Me | 3-methylisoxazol-5-yl | 0.93 | 254 | 3818 |
RTI-180 | I | 3-methylisoxazol-5-yl | 0.73 | 67.9 | 36.4 |
RTI-177 β-CPPIT 32g | Cl | 3-phenylisoxazol-5-yl | 1.28 ± 0.18 | 504 ± 29 | 2420 ± 136 |
RTI-176 | Me | 3-phenylisoxazol-5-yl | 1.58 | 398 | 5110 |
RTI-181 | I | 3-phenylisoxazol-5-yl | 2.57 | 868 | 100 |
RTI-184 | H | methyl | 43.3 | — | 6208 |
RTI-185 | H | Ph | 285 | — | >12K |
RTI-334 | Cl | 3-ethylisoxazol-5-yl | 0.50 | 120 | 3086 |
RTI-335 | Cl | isopropyl | 1.19 | 954 | 2318 |
RTI-336 | Cl | 3-(4-methylphenyl)isoxazol-5-yl | 4.09 | 1714 | 5741 |
RTI-337 | Cl | 3-t-butyl-isoxazol-5-yl | 7.31 | 6321 | 37K |
RTI-345 | Cl | p-chlorophenyl | 6.42 | 5290 | >76K |
RTI-346 | Cl | p-anisyl | 1.57 | 762 | 5880 |
RTI-347 | Cl | p-fluorophenyl | 1.86 | 918 | 7257 |
RTI-354 | Me | 3-ethylisoxazol-5-yl | 1.62 | 299 | 6400 |
RTI-366 | Me | R = isopropyl | 4.5 | 2523 (1550) | 42,900 (3900) |
RTI-371 | Me | p-chlorophenyl | 8.74 | >100K (60,200) | >100K (9090) |
RTI-386 | Me | p-anisyl | 3.93 | 756 (450) | 4027 (380) |
RTI-387 | Me | p-fluorophenyl | 6.45 | 917 (546) | >100K (9400) |
3-Substituted-1,2,4-oxadiazole
[edit]Structure | Code (Singh's #) | X | R | DAT (IC50 nM) displacement of [H3]WIN 35428 | NET (IC50 nM) [H3]nisoxetine | 5-HTT (IC50 nM) [H3]paroxetine | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|
ααRTI-87 | H | 3-methyl-1,2,4-oxadiazole | 204 | 36K | 30K | |||
βαRTI-119 | H | 3-methyl-1,2,4-oxadiazole | 167 | 7K | 41K | |||
αβRTI-124 | H | 3-methyl-1,2,4-oxadiazole | 1028 | 71K | 33K | |||
RTI-125 (32a) | Cl | 3-methyl-1,2,4-oxadiazole | 4.05 ± 0.57 | 363 ± 36 | 2584 ± 800 | 637 | 89.6 | |
ββRTI-126[18] (31) | H | 3-methyl-1,2,4-oxadiazole | 100 ± 6 | 7876 ± 551 | 3824 ± 420 | 38.3 | 788 | |
RTI-130 (32c) | Cl | 3-phenyl-1,2,4-oxadiazole | 1.62 ± 0.02 | 245 ± 13 | 195 ± 5 | 120 | 151 | |
RTI-141 (32d) | Cl | 3-(p-anisyl)-1,2,4-oxadiazole | 1.81 ± 0.19 | 835 ± 8 | 337 ± 40 | 186 | 461 | |
RTI-143 (32e) | Cl | 3-(p-chlorophenyl)-1,2,4-oxadiazole | 4.06 ± 0.22 | 40270 ± 180 (4069) | 404 ± 56 | 99.5 | 9919 | |
RTI-144 (32f) | Cl | 3-(p-bromophenyl)-1,2,4-oxadiazole | 3.44 ± 0.36 | 1825 ± 170 | 106 ± 10 | 30.8 | 532 | |
βRTI-151 (33) | Me | 3-phenyl-1,2,4-oxadiazole | 2.33 ± 0.26 | 60 ± 2 | 1074 ± 130 | 459 | 25.7 | |
αRTI-152 | Me | 3-phenyl-1,2,4-oxadiazole | 494 | — | 1995 | |||
RTI-154 (32b) | Cl | 3-isopropyl-1,2,4-oxadiazole | 6.00 ± 0.55 | 135 ± 13 | 3460 ± 250 | 577 | 22.5 | |
RTI-155 | Cl | 3-cyclopropyl-1,2,4-oxadiazole | 3.41 | 177 | 4362 |
Structure | Code | X | 2 Group | DAT (IC50 nM) displacement of [H3]WIN 35428 | NET (IC50 nM) displacement of [H3]nisoxetine | 5-HTT (IC50 nM) displacement of [H3]paroxetine | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|
RTI-157 | Me | tetrazole | 1557 | >37K | >43K | |||
RTI-163 | Cl | tetrazole | 911 | — | 5456 | |||
RTI-178 | Me | 5-phenyl-oxazol-2-yl | 35.4 | 677 | 1699 | |||
RTI-188 | Cl | 5-phenyl-1,3,4-oxadiazol-2-yl | 12.6 | 930 | 3304 | |||
RTI-189 (32i) | Cl | 5-phenyl-oxazol-2-yl | 19.7 ± 1.98 | 496 ± 42 | 1120 ± 107 | 56.8 | 25.5 | |
RTI-194 | Me | 5-methyl-1,3,4-oxadiazol-2-yl | 4.45 | 253 | 4885 | |||
RTI-195 | Me | 5-phenyl-1,3,4-oxadiazol-2-yl | 47.5 | 1310 | >22,000 | |||
RTI-199 | Me | 5-phenyl-1,3,4-thiadiazol-2-yl | 35.9 | >24,000 | >51,000 | |||
RTI-200 | Cl | 5-phenyl-1,3,4-thiadiazol-2-yl | 15.3 | 4142 | >18,000 | |||
RTI-202 | Cl | benzothiazol-2-yl | 1.37 | 403 | 1119 | |||
RTI-219 | Cl | 5-phenylthiazol-2-yl | 5.71 | 8516 | 10,342 | |||
RTI-262 | Cl | 188.2 ± 5.01 | 595.25 ± 5738 | 5207 ± 488 | 316 | 28 | ||
RTI-370 | Me | 3-(p-cresyl)isoxazol-5-yl | 8.74 | 6980 | >100K | |||
RTI-371 | Cl | 3-(p-chlorophenyl)isoxazol-5-yl | 13 | >100K | >100K | |||
RTI-436 | Me | -CH=CHPh[20] | 3.09 | 1960 (1181) | 335 (31) | |||
RTI-470 | Cl | o-Cl-benzothiazol-2-yl | 0.094 | 1590 (994) | 1080 (98) | |||
RTI-451 | Me | benzothiazol-2-yl | 1.53 | 476 (287) | 7120 (647) | |||
32g | 1.28 ± 0.18 | 504 ± 29 | 2420 ± 136 | 1891 | 394 | |||
32h | 12.6 ± 10.3 | 929 ± 88 | 330 ± 196 | 262 | 73.7 |
N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).
Acyl (C2-propanoyl)
[edit]# (#) | X | Y | 2 Position | config | 8 | DA | 5-HT | NE |
---|---|---|---|---|---|---|---|---|
WF-23 (39n) | β-naphthyl | C(O)Et | β,β | NMe | 0.115 | 0.394 | No data | |
WF-31 PIT | -Pri | H | C.O.Et | β,β | NMe | 615 | 54.5 | No data |
WF-11✲ PTT (39e) | Me | H | -C.O.Et | β,β | NMe | 8.2 | 131 | No data |
WF-25 (39a) | H | H | -C.O.Et | β,β | NMe | 48.3 | 1005 | No data |
WF-33 | 6-MeoBN | C(O)Et | α,β | NMe | 0.13 | 2.24 | No data | |
✲Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration) |
Structure | S. Singh's alphanumeric assignation (name) | R1 | R2 | DAT [125I]RTI-55 IC50 (nM) | 5-HTT [3H]Paroxetine Ki (nM) | Selectivity 5-HTT/DAT |
---|---|---|---|---|---|---|
cocaine | 173 ± 19 | — | — | |||
Troparil 11a (WIN 35065-2) | 98.8 ± 12.2 | — | — | |||
WF-25 39a | C2H5 | C6H5 | 48.3 ± 2.8 | 1005 ± 112 | 20.8 | |
39b | CH3 | C6H5 | 114 ± 22 | 1364 ± 616 | 12.0 | |
39c | C2H5 | C6H4-4-F | 15.3 ± 2.8 | 630 ± 67 | 41.2 | |
39d | CH3 | C6H4-4-F | 70.8 ± 13 | 857 ± 187 | 12.1 | |
WF-11 39e | C2H5 | C6H4-4-CH3 | 8.2 ± 1.6 | 131 ± 1 | 16.0 | |
(+)-39e | C2H5 | C6H4-4-CH3 | 4.21 ± 0.05 | 74 ± 12 | 17.6 | |
(-)-39e | C2H5 | C6H4-4-CH3 | 1337 ± 122 | >10000 | — | |
39f | CH3 | C6H4-4-CH3 | 9.8 ± 0.5 | 122 ± 22 | 12.4 | |
39g | CH3 | C6H4-4-C2H5 | 152 ± 24 | 78.2 ± 22 | 0.5 | |
39h | C2H5 | C6H4-4-CH(CH3)2 | 436 ± 41 | 35.8 ± 4.4 | 0.08 | |
39i | C2H5 | C6H4-4-C(CH3)3 | 2120 ± 630 | 1771 ± 474 | 0.8 | |
39j | C2H5 | C6H4-4-C6H5 | 2.29 ± 1.08 | 4.31 ± 0.01 | 1.9 | |
39k | C2H5 | C6H4-2-CH3 | 1287 ± 322 | 710000 | >7.8 | |
39l | C2H5 | 1-naphthyl | 5.43 ± 1.27 | 20.9 ± 2.9 | 3.8 | |
39m | CH3 | 1-naphthyl | 10.1 ± 2.2 | 25.6 ± 5.1 | 2.5 | |
WF-23 39n | C2H5 | 2-naphthyl | 0.115 ± 0.021 | 0.394 ± 0.074 | 3.5 | |
39o | CH3 | 2-naphthyl | 0.28 ± 0.11 | 1.06 ± 0.36 | 3.8 | |
39p | C2H5 | C6H4-4-CH(C2H5)2 | 270 ± 38 | 540 ± 51 | 2.0 | |
39q | C2H5 | C6H4-4-C6H11 | 320 ± 55 | 97 ± 12 | 0.30 | |
39r | C2H5 | C6H4-4-CH=CH2 | 0.90 ± 0.34 | 3.2 ± 1.3 | 3.5 | |
39s | C2H5 | C6H4-4-C(=CH2)CH3 | 7.2 ± 2.1 | 0.82 ± 0.38 | 0.1 |
2β-Acyl-3β-naphthyl substituted
[edit]Structure | Short Assignation (Numeric code, Davies UB) S. Singh | R | DAT [125H]RTI-55ɑ IC50 nM | SERT [3H]paroxetineb Ki nM | NET [3H]nisoxetinec Ki nM | potency ratio SERT/DAT | potency ratio SERT/NET |
---|---|---|---|---|---|---|---|
WF-11 (6) | 4′-Me | 8.2 ± 1.6 | 131 ± 10 | 65 ± 9.2 | 0.06 | 0.5 | |
WF-31 (7) | 4′-iPr | 436 ± 41 | 36 ± 4 | >10,000 | 12 | >250 | |
WF-23 (8) | 2-naphthalene | 0.12 ± 0.02 | 0.39 ± 0.07 | 2.9 ± 0.5 | 0.3 | 7 | |
2β-acyl-3β-1-naphthalene (9a) | 4′-H | 5.3 ± 1.3 | 21 ± 2.9 | 49 ± 10 | 0.3 | 18 | |
(9b) | 4′-Me | 25.1 ± 0.5 | 8.99 ± 1.70 | 163 ± 36 | 3 | 18 | |
(9c) | 4′-Et | 75.1 ± 11.9 | 175 ± 25 | 4769 ± 688 | 0.7 | 27 | |
(9d) | 4′-iPr | 225 ± 36 | 136 ± 64 | >10,000 | 2 | >73.5 | |
(10a) | 6′-Et | 0.15 ± 0.04 | 0.38 ± 0.19 | 27.7 ± 9.6 | 0.4 | 74 | |
(10b) | 6′-iPr | 0.39 ± 0.04 | 1.97 ± 0.33 | no data | 0.2 | — | |
(10ce) | 6′- OMe | 0.13 ± 0.04 | 2.24 ± 0.34 | no data | 0.05 | — | |
(10d) | 5′-Et, 6′-OMe | 30.8 ± 6.6 | 7.55 ± 1.57 | 3362 ± 148 | 4.1 | 445 | |
(10e) | 5′-C(Me)=CH2, 6′-OMe | 45.0 ± 3.7 | 88.0 ± 13.3 | 2334 ± 378 | 0.5 | 26.5 | |
(10f) | 6′-I | 0.35 ± 0.07 | 0.37 ± 0.02 | no data | 1.0 | — | |
(10g) | 7′-I | 0.45 ± 0.05 | 0.47 ± 0.02 | no data | 0.5d | — | |
(10h) | 5′-NO2, 6′-OMe | 148 ± 50 | 15 ± 1.6 | no data | 10 | — | |
(10i) | 5′-I, 6′-OMe | 1.31 ± 0.33 | 2.27 ± 0.31 | 781 ± 181 | 0.6 | 344 | |
(10j) | 5′-COMe, 6′-OMe | 12.6 ± 3.8 | 15.8 ± 1.65 | 498 ± 24 | 0.8 | 32 | |
(11a) | 2β-COCH3, 1-naphthyl | 10 ± 2.2 | 26 ± 5.1 | 165 ± 40 | 0.4 | 6.3 | |
(11b) | 2α-COCH3, 1-naphthyl | 97 ± 21 | 217 ± 55 | no data | 0.45 | — | |
(11c) | 2α-COCH2CH3, 2-naphthyl | 2.51 ± 0.82 | 16.4 ± 2.0 | 68.0 ± 10.8 | 0.15 | 4.1 | |
(11d) | 2β-COCH3, 2-naphthyl | 1.27 ± 0.15 | 1.06 ± 0.36 | 4.9 ± 1.2 | 1.2 | 4.6 | |
(11e) | 2β-COCH(CH3)2, 2-naphthyl | 0.25 ± 0.08 | 2.08 ± 0.80 | 37.6 ± 10.5 | 0.12 | 18.1 | |
(11f) 79a | 2β-COCH2CH3, 2-naphthyl, N8-demethyl | 0.03 ± 0.01 | 0.23 ± 0.07 | 2.05 ± 0.9 | 0.13 | 8.9 |
|
|
Ester reduction
[edit]Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.
Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
---|---|---|---|---|---|---|---|
RTI-100 | F | -CH2OH | β,β | NMe | 47 | 4741 | no data |
RTI-101 | I | -CH2OH | β,β | NMe | 2.2 | 26 | no data |
RTI-99 | Br | -CH2OH | β,β | NMe | 1.49 | 51 | no data |
RTI-93 | Cl | -CH2OH | β,β | NMe | 1.53 | 204 | 43.8 |
RTI-105 | Cl | -CH2OAc | β,β | NMe | 1.60 | 143 | 127 |
RTI-123 | Cl | -CH2OBz | β,β | NMe | 1.78 | 3.53 | 393 |
RTI-145 | Cl | -CH2OCO2Me | β,β | NMe | 9.60 | 2.93 | 1.48 |
2-Alkane/Alkene
[edit]Structure | Singh's # | R | X | DAT mazindol displacement | DA uptake | 5-HT Uptake | Selectivity DA uptake/DAT binding |
---|---|---|---|---|---|---|---|
11a WIN 35062-2 | 89.4 | 53.7 | 186 | 0.6 | |||
11c | 0.83 ± 00.7 | 28.5 ± 0.9 | — | 34.3 | |||
11f | 5.76 | 6.92 | 23.2 | 1.2 | |||
41a | (CH2)2CH3 | H | 12.2 | 6.89 | 86.8 | 0.6 | |
41b | (CH2)3C6H5 | H | 16 ± 2a | 43 ± 13b | — | 2.7 | |
42 | (CH2)2CH3 | F | 5.28 | 1.99 | 21.7 | 0.4 | |
43a | CH=CH2 | Cl | 0.59 ± 0.15 | 2.47 ± 0.5 | — | 4.2 | |
43b | E-CH=CHCl | Cl | 0.42 ± 0.04 | 1.13 ± 0.27 | — | 2.7 | |
43c | Z-CH=CHCl | Cl | 0.22 ± 0.02 | 0.88 ± 0.05 | — | 4.0 | |
43d | E-CH=CHC6H5 | Cl | 0.31 ± 0.04 | 0.66 ± 0.01 | — | 2.1 | |
43e | Z-CH=CHC6H5 | Cl | 0.14 ± 0.07 | 0.31 ± 0.09 | — | 2.2 | |
43f | CH2CH3 | Cl | 2.17 ± 0.20 | 2.35 ± 0.52 | — | 1.1 | |
43 g | (CH2)2CH3 | Cl | 0.94 ± 0.08 | 1.08 ± 0.05 | — | 1.1 | |
43h | (CH2)3CH3 | Cl | 1.21 ± 0.18 | 0.84 ± 0.05 | — | 0.7 | |
43i | (CH2)5CH3 | Cl | 156 ± 15 | 271 ± 3 | — | 1.7 | |
43j | (CH2)2C6H5 | Cl | 1.43 ± 0.03 | 1.54 ± 0.08 | — | 1.0 | |
44a | (CH2)2CH3 | CH3 | 1.57 | 1.10 | 10.3 | 0.7 | |
44b | (CH2)3CH3 | CH3 | 1.82 | 1.31 | 15.1 | 0.7 | |
45 | (CH2)2CH3 | H | 74.9 | 30.2 | 389 | 0.4 | |
46 | (CH2)2CH3 | F | 21.1 | 12.1 | 99.6 | 0.6 | |
47a | (CH2)2CH3 | CH3 | 8.91 | 11.8 | 50.1 | 1.3 | |
47b | (CH2)3CH3 | CH3 | 11.4 | 10.1 | 51.0 | 0.9 |
aKi value for displacement of WIN 35428.
bIC50 value.
Irreversible covalent (cf. ionic) C2 ligands
[edit]
Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics. 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID 18492949. S2CID 5996473.)[23] RTI-76:[24] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.
C2 Acyl, N8 phenylisothiocyanate
[edit]
HD-205 (Murthy et al., 2007)[25]
Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.
Benztropine based (C2-position hetero-substituted) phenyltropanes
[edit]Structure | Compound | R | X | Y | [3H]WIN 35,428 @ DAT Ki (nM) | [3H]Citalopram @ SERT Ki (nM) | [3H]Nisoxetine @ NET Ki (nM) | [3H]Pirenzepine @ M1 Ki (nM) |
---|---|---|---|---|---|---|---|---|
9a | CH3 | H | H | 34 ± 2 | 121 ± 19 | 684 ± 100 | 10,600 ± 1,100 | |
9b | F | H | H | 49 ± 12 | — | — | — | |
9c | Cl | H | H | 52 ± 2.1 | 147 ± 8 | 1,190 ± 72 | 11,000 ± 1,290 | |
9d | CH3 | Cl | H | 80 ± 9 | 443 ± 60 | 4,400 ± 238 | 31,600 ± 4,300 | |
9e | F | Cl | H | 112 ± 11 | — | — | — | |
9f | Cl | Cl | H | 76 ± 7 | 462 ± 36 | 2,056 ± 236 | 39,900 ± 5,050 | |
9g | CH3 | F | F | 62 ± 7 | 233 ± 24 | 1,830 ± 177 | 15,500 ± 1,400 | |
9h | F | F | F | 63 ± 13 | — | — | — | |
9i | Cl | F | F | 99 ± 18 | 245 ± 16 | 2,890 ± 222 | 16,300 ± 1,300 | |
10a | CH3 | H | H | 455 ± 36 | 530 ± 72 | 2,609 ± 195 | 12,600 ± 1,790 | |
10c | Cl | H | H | 478 ± 72 | 408 ± 16 | 3,998 ± 256 | 11,500 ± 1,720 | |
10d | CH3 | Cl | H | 937 ± 84 | 1,001 ± 109 | 22,500 ± 2,821 | 18,200 ± 2,600 | |
10f | Cl | Cl | H | 553 ± 106 | 1,293 ± 40 | 5,600 ± 183 | 9,600 ± 600 | |
10g | CH3 | F | F | 690 ± 76 | 786 ± 67 | 16,000 ± 637 | 9,700 ± 900 | |
10i | Cl | F | F | 250 ± 40 | 724 ± 100 | 52,300 ± 13,600 | 9,930 ± 1,090 | |
12a | H | H | H | 139 ± 15 | 61 ± 9 | 207 ± 30 | 7,970 ± 631 | |
12b | H | Cl | H | 261 ± 19 | 45 ± 3 | — | 24,600 ± 2,930 | |
12c | H | F | F | 60 ± 7 | — | — | — |
F&B series (Biotin side-chains etc.)
[edit]One patent claims a series of compounds with biotin-related sidechains are pesticides.[18]
Images of the biotin C2 side-chained phenyltropanes, click to |
---|
Structure | Code | para-X | C2-Tropane Position | config | DA | NE | 5-HT |
---|---|---|---|---|---|---|---|
— | H | F1 | β,β | — | — | — | |
RTI-224 | Me | F1c | β,β | 4.49 | — | 155.6 | |
RTI-233 | Me | F2 | β,β | 4.38 | 516 | 73.6 | |
RTI-235 | Me | F3d | β,β | 1.75 | 402 | 72.4 | |
— | — | F3 | β,β | — | — | — | |
RTI-236 | Me | B1d | β,β | 1.63 | 86.8 | 138 | |
RTI-237 | Me | B2d | β,β | 7.27 | 258 | 363 | |
RTI-244 | Me | B3d | β,β | 15.6 | 1809 | 33.7 | |
RTI-245 | Cl | F4c | β,β | 77.3 | — | — | |
RTI-246 | Me | F4c | β,β | 50.3 | 3000 | — | |
— | — | F5 | β,β | — | — | — | |
RTI-248 | Cl | F6c | β,β | 9.73 | 4674 | 6.96 | |
RTI-249 | Cl | F1c | β,β | 8.32 | 5023 | 81.6 | |
RTI-266 | Me | F2 | β,β | 4.80 | 836 | 842 | |
RTI-267 | Me | F7 wrong | β,β | 2.52 | 324 | 455 | |
RTI-268 | Me | F7 right | β,β | 3.89 | 1014 | 382 | |
RTI-269 | Me | F8 | β,β | 5.55 | 788 | 986 |
Miscellany (i.e. Misc./Miscellaneous) C2-substituents
[edit]Structure | Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
---|---|---|---|---|---|---|---|---|
RTI-102 | I | CO2H | β,β | NMe | 474 | 1928 | 43,400 | |
RTI-103 | Br | CO2H | β,β | NMe | 278 | 3070 | 17,400 | |
RTI-104 | F | CO2H | β,β | NMe | 2744 | >100K | >100K | |
RTI-108 | Cl | -CH2Cl | β,β | NMe | 2.64 | 98 | 129.8 | |
RTI-241 | Me | -CH2CO2Me | β,β | NMe | 1.02 | 619 | 124 | |
RTI-139 | Cl | -CH3 | β,β | NMe | 1.67 | 85 | 57 | |
RTI-161 | Cl | -C≡N | β,β | NMe | 13.1 | 1887 | 2516 | |
RTI-230 | Cl | H3C–C=CH2 | β,β | NMe | 1.28 | 57 | 141 | |
RTI-240 | Cl | -CHMe2 | β,β | NMe | 1.38 | 38.4 | 84.5 | |
RTI-145 | Cl | -CH2OCO2Me | β,β | NMe | 9.60 | 2,932 | 1,478 | |
RTI-158 | Me | -C≡N | β,β | NMe | 57 | 5095 | 1624 | |
RTI-131 | Me | -CH2NH2 | β,β | NMe | 10.5 | 855 | 120 | |
RTI-164 | Me | -CH2NHMe | β,β | NMe | 13.6 | 2246 | 280 | |
RTI-132 | Me | -CH2NMe2 | β,β | NMe | 3.48 | 206 | 137 | |
RTI-239 | Me | -CHMe2 | β,β | NMe | 0.61 | 114 | 35.6 | |
RTI-338 | Et | -CO2CH2Ph | β,β | NMe | 1104 | 7.41 | 3366 | |
RTI-348 | H | -Ph | β,β | NMe | 28.2 | >34,000 | 2670 |
C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes)
[edit]Aryl-Tropenes
[edit]WO 2004113297, Peters, Dan; Olsen, Gunnar M. & Nielsen, Elsebet Oestergaard et al., "Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-12-29, assigned to NeuroSearch AS
Test compound | DA-uptake IC50(μM) | NA-uptake IC50(μM) | 5-HT-uptake IC50(μM) |
---|---|---|---|
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene | 0.26 | 0.028 | 0.010 |
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene | 0.058 | 0.013 | 0.00034 |
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene | 0.034 | 0.018 | 0.00023 |
Test Compound | DA uptake IC50(μM) | NE uptake IC50(μM) | 5-HT uptake IC50(μM) |
---|---|---|---|
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 0.079 | 0.026 | 0.0047 |
Test Compound | DA uptake IC50(μM) | NE uptake IC50(μM) | 5-HT uptake IC50(μM) |
---|---|---|---|
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 18 | 4.9 | 0.047 |
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 1.5 | 0.5 | 0.016 |
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 22.00 | 8.00 | 0.0036 |
Enantioselective nonstandard configurations (non-2β-,3β-)
[edit]β,α Stereochemistry
[edit]Structure | Compound (RTI #) (S. Singh's #) | X | 2 Group | config | 8 | DAT IC50 (nM) [3H]WIN 35428 | 5-HTT IC50 (nM) [3H]paroxetine | NET IC50 (nM) [3H]nisoxetine | selectivity 5-HTT/DAT | selectivity NET/DAT |
---|---|---|---|---|---|---|---|---|---|---|
RTI-140 20a | H | CO2Me | β,α | NMe | 101 ± 16 | 5,701 ± 721 | 2,076 ± 285 | 56.4 | 20.6 | |
RTI-352ɑ 20d | I | CO2Me | β,α | NMe | 2.86 ± 0.16 | 64.9 ± 1.97 | 52.4 ± 4.9 | 22.8 | 18.4 | |
RTI-549 | Br | CO2Me | β,α | NMe | — | — | — | — | — | |
RTI-319b | 3α-2-naphthyl | CO2Me | β,α | NMe | 1.1 ± 0.09 | 11.4 ± 1.3 | 70.2 ± 6.28 | — | — | |
RTI-286c 20b | F | CO2Me | β,α | NMe | 21 ± 0.57 | 5062 ± 485 | 1231 ± 91 | 241 | 58.6 | |
RTI-274d | F | CH2O(3′,4′-MD-phenyl) | β,α | NH | 3.96 | 5.62 | 14.4 | — | — | |
RTI-287 | Et | CO2Me | β,α | NMe | 327 | 1687 | 17,819 | — | — | |
20c | Cl | CO2Me | β,α | NMe | 2.4 ± 0.2 | 998 ± 120 | 60.1 ± 2.4 | 416 | 25.0 | |
20e | Me | CO2Me | β,α | NMe | 10.2 ± 0.08 | 4250 ± 422 | 275 ± 24 | 417 | 27.0 | |
Bn | CO2Me | β,α | NMe | — | — | — | — | — |
α,β Stereochemistry
[edit]Compound | DA (μM) | M.E.D. (mg/kg) | Dose (mg/kg) | Activity | Activity |
---|---|---|---|---|---|
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane | 0.39 | <1 | 50 | 0 | 0 |
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane | 0.1 | 1 | 25 | 0 | 0 |
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane | 0.016 | 0.25 | 50 | + | +++ |
di-chloro; para- & meta- in tandem (α,β configured phenyltropanes)
[edit]Compound | X | 2 Group | config | 8 | DA | 5-HT | NE |
---|---|---|---|---|---|---|---|
Brasofensine | Cl2 | methyl aldoxime | α,β | NMe | — | — | — |
Tesofensine | Cl2 | ethoxymethyl | α,β | NMe | 65 | 11 | 1.7 |
NS-2359 (GSK-372,475) | Cl2 | Methoxymethyl | α,β | NH | — | — | — |
fumaric acid salts (of α,β configured phenyltropanes)
[edit]WO 2004072075, Peters, Dan; Nielsen, Elsebet Oestergaard & Olsen, Gunnar M. et al., "Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-08-26, assigned to NeuroSearch AS
Test Compound | DA uptake IC50(μM) | NE uptake IC50(μM) | 5-HT uptake IC50(μM) |
---|---|---|---|
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.062 | 0.035 | 0.00072 |
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.062 | 0.15 | 0.0063 |
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.10 | 0.048 | 0.0062 |
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.088 | 0.051 | 0.013 |
Arene equivalent alterations
[edit]η6-3β-(transition metal complexed phenyl)tropanes
[edit]Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule.[1] (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.[29]).
21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity Ki values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.
The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.[1]
Structure | Compound # (S. Singh) Systematic name | Ki (nM)ɑ | IC50 (nM) | selectivity binding/uptake |
---|---|---|---|---|
21ac | 17 ± 15b 224 ± 83 | 418 | 24.6 | |
21bd | 2280 ± 183 | 3890 | 1.7 | |
Cocaine | 32 ± 5 388 ±221 | 405 | 12.6 | |
Troparil (11a) | 33 ± 17 314 ± 222 | 373 | 11.3 |
- ɑThe binding data fit a two-site model better than a one-site model
- bThe Ki value for the one-site model was 124 ± 10 nM
- cIUPAC: [η6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
- dIUPAC: [η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate
3-(2-thiophene) and 3-(2-furan)
[edit]Code | Compound | DA (μM) | NE (μM) | 5-HT (μM) |
---|---|---|---|---|
1 | (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt | 0.30 | 0.0019 | 0.00052 |
2 | (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt | 0.36 | 0.0036 | 0.00042 |
3 | (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt | 0.31 | 0.00090 | 0.00036 |
4 | (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt | 0.92 | 0.0030 | 0.00053 |
5 | (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt | 0.074 | 0.0018 | 0.00074 |
6 | (2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt | 0.19 | 0.0016 | 0.00054 |
Thiophenyltropanes
[edit]Diaryl
[edit]6/7-tropane position substituted
[edit]2β-carbomethoxy 6/7 substituted
[edit]Structure | Compound # (S. Singh) | Substitution | DAT (IC50 nM) displacement of [H3]WIN 35428 | 5-HTT (IC50 nM) [H3]Citalopram | Selectivity 5-HTT/DAT |
---|---|---|---|---|---|
Cocaine | H | 65 ± 12 | - | - | |
103a | 3β,2β, 7-OMe 3′,4′-Cl2 | 86 ± 4.7 | 884 ± 100 | 10.3 | |
103b | 3β,2β, 7-OH 3′,4′-Cl2 | 1.42 ± 0.03 | 28.6 ± 7.8 | 20.1 | |
103c | 3α,2β, 7-OH 3′,4′-Cl2 | 1.19 ± 0.16 | 1390 ± 56 | 1168 | |
104a | 3β,2β, 6-OH 4′-Me | 215ɑ | - | - | |
104b | 3β,2α, 6-OH 4′-Me | 15310ɑ | - | - | |
104c | 3α,2β, 6-OH 4′-Me | 930ɑ | - | - | |
104d | 3α,2α, 6-OH 4′-Me | 7860ɑ | - | - |
- ɑIC50 value for displacement of [H3]mazindol. IC50 for cocaine 288 nM for displacement of [H3]mazindol
3-butyl 6/7 substituted
[edit]Structure | Compound # (S. Singh) | Substituent | Ki nM displacement of [H3]mazindol binding | Ki nM [H3]DA uptake | Selectivity uptake/binding |
---|---|---|---|---|---|
Cocaine | H | 270 ± 0.03 | 400 ± 20 | 1.5 | |
121a | 7β-CN | 2020 ± 10 | 710 ± 40 | 0.3 | |
121b | 6β-CN | 3040 ± 480 | 6030 ± 880 | 2.0 | |
121c | 7β-SO2Ph | 4010 ± 310 | 8280 ± 1340 | 2.1 | |
121d | 6β-SO2Ph | 4450 ± 430 | 8270 ± 690 | 1.8 | |
121e | 7α-OH | 830 ± 40 | 780 ± 60 | 0.9 | |
121f | H | 100 ± 10 | 61 ± 10 | 0.6 | |
121g | 7β-CN | 24000 ± 3420 | 32100 ± 8540 | 1.3 | |
121h | 6β-CN | 11300 ± 1540 | 26600 ± 3330 | 2.3 | |
121i | 7β-SO2Ph | 7690 ± 2770 | 7050 ± 450 | 0.9 | |
121j | 6β-SO2Ph | 4190 ± 700 | 8590 ± 1360 | 2.0 | |
121k | 7α-SO2Ph | 3420 ± 1100 | - | - | |
121l | 7β-SO2Ph, 7α-F | 840 ± 260 | 2520 ± 290 | 3.0 | |
121m | 7α-F | 200 ± 10 | 680 ± 10 | 3.4 | |
121n | 7β-F | 500 ± 10 | 550 ± 140 | 1.1 |
intermediate 6- & 7-position synthesis modified phenyltropanes
[edit]Structure | Compound # (S. Singh) | Substituent W | Substituent X | Substituent Y | Substituent Z |
---|---|---|---|---|---|
(±)-122a | CN | H | H | H | |
(±)-122b | H | H | CH | H | |
(±)-122c | H | CH | H | H | |
(±)-122d | H | H | H | CH | |
(±)-122e | SO2Ph | H | H | H | |
(±)-122f | H | H | SO2Ph | H | |
(±)-122g | H | SO2Ph | H | H | |
(±)-122h | SO2Ph | F | H | H | |
(±)-122i | F | SO2Ph | H | H | |
(±)-122j | H | H | SO2Ph | F |
8-tropane (bridgehead) position modified
[edit]Nortropanes (N-demethylated)
[edit]NS2359 (GSK-372,475)
It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.[33] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.[34]
Code (S.S. #) | X para (unless position otherwise given inline) | DA | 5HT | NE |
---|---|---|---|---|
RTI-142 75b | F | 4.39 | 68.6 | 18.8 |
RTI-98 75d Norɑ-RTI-55 | I | 0.69 | 0.36 | 11.0 |
RTI-110 75c | Cl | 0.62 | 4.13 | 5.45 |
RTI-173 75f | Et | 49.9 | 8.13 | 122 |
RTI-279 Norɑ-RTI-280 | para-Me meta-I | 5.98 ± 0.48 | 1.06 ± 0.10 | 74.3 ± 3.8 |
RTI-305 Norɑ-RTI-360/11y | Ethynyl | 1.24 ± 0.11 | 1.59 ± 0.2 | 21.8 ± 1.0 |
RTI-307 Norɑ-RTI-281/11z | Propynyl | 6.11 ± 0.67 | 3.16 ± 0.33 | 115.6 ± 5.1 |
RTI-309 Norɑ-11t | Vinyl | 1.73 ± 0.05 | 2.25 ± 0.17 | 14.9 ± 1.18 |
RTI-330 Norɑ-11s | Isopropyl | 310.2 ± 21 | 15.1 ± 0.97 | — |
RTI-353 | para-Et meta-I | 330.54 ± 17.12 | 0.69 ± 0.07 | 148.4 ± 9.15 |
ɑThe N-demethylated variant of (i.e. compound code-name after dash)
N-Me compound code# → N-demethylated derivative compound code # | para-X | [3H]Paroxetine | [3H]WIN 35,428 | [3H]Nisoxetine |
---|---|---|---|---|
11 g→75f | Ethyl | 28.4 → 8.13 | 55 → 49.9 | 4,029 → 122 |
11t→75i | Vinyl | 9.5 → 2.25 | 1.24 → 1.73 | 78 → 14.9 |
11y→75n | Ethynyl | 4.4 → 1.59 | 1.2 → 1.24 | 83.2 → 21.8 |
11r→75 g | 1-Propyl | 70.4 → 26 | 68.5 → 212 | 3,920 → 532 |
11v→75k | trans-propenyl | 11.4 → 1.3 | 5.29 → 28.6 | 1,590 → 54 |
11w→75l | cis-propenyl | 7.09 → 1.15 | 15 → 31.6 | 2,800 → 147 |
11x→75 m | Allyl | 28.4 → 6.2 | 32.8 → 56.5 | 2,480 → 89.7 |
11z→75o | 1-Propynyl | 15.7 → 3.16 | 2.37 → 6.11 | 820 → 116 |
11s→75h | i-Propyl | 191 → 15.1 | 597 → 310 | 75,000 → ? |
11u→75j | 2-Propenyl | 3.13 → 0.6 | 14.4 → 23 | 1,330? → 144 |
Isomer | 4′ | 3′ | NE | DA | 5HT |
---|---|---|---|---|---|
β,β | Me | H | 60 → 7.2 | 1.7 → 0.84 | 240 → 135 |
β,β | F | H | 835 → 18.8 | 15.7 → 4.4 | 760 → 68.6 |
β,β | Cl | H | 37 → 5.45 | 1.12 → 0.62 | 45 → 4.13 |
β,α | Me | H | 270 → 9 | 10.2 → 33.6 | 4250 → 500 |
β,α | F | H | 1200 → 9.8 | 21 → 32.6 | 5060 → 92.4 |
β,α | Cl | H | 60 → 5.41 | 2.4 → 3.1 | 998 → 53.3 |
β,α | F | Me | 148 → 4.23 | 13.7 → 9.38 | 1161 → 69.8 |
β,α | Me | F | 44.7 → 0.86 | 7.38 → 9 | 1150 → 97.4 |
"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).[35]
Structure | Short Name (S. Singh) | Para-X | DAT [3H]WIN 35428 IC50 (nM) | 5-HTT [3H]Paroxetine IC50 (nM) | NET [3H]Nisoxetine IC50 (nM) | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|
Norcocaine | H | 206 ± 29 | 127 ± 13 | 139 ± 9 | 0.6 | 0.7 | |
75a | H | 30.8 ± 2.3 | 156 ± 8 | 84.5 ± 7.5 | 5.1 | 2.7 | |
75b | F | 4.39 ± 0.20 | 68.6 ± 2.0 | 18.8 ± 0.7 | 15.6 | 4.3 | |
75c | Cl | 0.62 ± 0.09 | 4.13 ± 0.62 | 5.45 ± 0.21 | 6.7 | 8.8 | |
75d | I | 0.69 ± 0.2 | 0.36 ± 0.05 | 7.54 ± 3.19 | 0.5 | 10.9 | |
75e | para-I & 2β-CO2CH(CH3)2 | 1.06 ± 0.12 | 3.59 ± 0.27 | 132 ± 5 | 3.4 | 124 | |
75f | C2H5 | 49.9 ± 7.3 | 8.13 ± 0.30 | 122 ± 12 | 0.2 | 2.4 | |
75g | n-C3H7 | 212 ± 17 | 26 ± 1.3 | 532 ± 8.1 | 0.1 | 2.5 | |
75h | CH(CH3)2 | 310 ± 21 | 15.1 ± 0.97 | - | 0.05 | - | |
75i | CH=CH2 | 1.73 ± 0.05 | 2.25 ± 0.17 | 14.9 ± 1.18 | 1.3 | 8.6 | |
75j | C-CH3 ║ CH2 | 23 ± 0.9 | 0.6 ± 0.06 | 144 ± 12 | 0.03 | 6.3 | |
75k | trans-CH=CHCH3 | 28.6 ± 3.1 | 1.3 ± 0.1 | 54 ± 16 | 0.04 | 1.9 | |
75l | cis-CH=CHCH3 | 31.6 ± 2.2 | 1.15 ± 0.1 | 147 ± 4.3 | 0.04 | 4.6 | |
75m | CH2CH=CH2 | 56.5 ± 56 | 6.2 ± 0.3 | 89.7 ± 9.6 | 0.1 | 1.6 | |
75n | CH≡CH | 1.24 ± 0.11 | 1.59 ± 0.2 | 21.8 ± 1.0 | 1.3 | 17.6 | |
75o | CH≡CCH3 | 6.11 ± 0.67 | 3.16 ± 0.33 | 116 ± 5.1 | 0.5 | 19.0 | |
75pɑ | 3,4-Cl2 | 0.66 ± 0.24 | 1.4b | - | 2.1 | - |
ɑThese values determined in Cynomolgus monkey caudate-putamen bThe radioligand used for 5-HTT was [3H]citalopram
Compound Structure | Short Name (S. Singh) | DAT [125I]RTI-55 IC50 (nM) | 5-HTT [3H]Paroxetine Ki (nM) | NET [3H]Nisoxetine Ki (nM) | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|
79a | 0.07 ± 0.01 | 0.22 ± 0.16 | 2.0 ± 0.09 | 3.1 | 28.6 | |
79b | 4.7 ± 0.58 | 19 ± 1.4 | 5.5 ± 2.0 | 4.0 | 1.2 | |
79c | 380 ± 110 | 5.3 ± 1.0 | 3400 ± 270 | 0.01 | 8.9 | |
79d | 190 ± 17 | 150 ± 50 | 5100 ± 220 | 0.8 | 26.8 | |
79e | 490 ± 120 | 85 ± 16 | 4300 ± 1100 | 0.1 | 8.8 | |
79f | 1.5 ± 1.1 | 0.32 ± 0.06 | 10.9 ± 1.5 | 0.2 | 7.3 | |
79g | 16 ± 4.9 | 0.11 ± 0.02 | 94 ± 18 | 0.07 | 5.9 |
Paroxetine homologues
[edit]See the N-methyl paroxetine homologues cf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.
Compound Structure | Short Name (S. Singh) | Stereochemistry | DAT [3H]WIN 35428 IC50 (nM) | 5-HTT [3H]Paroxetine IC50 (nM) | NET [3H]Nisoxetine IC50 (nM) | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|
Paroxetine | - | 623 ± 25 | 0.28 ± 0.02 | 535 ± 15 | 0.0004 | 0.8 | |
R-81a | 2β,3β | 835 ± 90 | 480 ± 21 | 37400 ± 1400 | 0.6 | 44.8 | |
R-81b | 2α,3β | 142 ± 13 | 90 ± 3.4 | 2500 ± 250 | 0.6 | 17.6 | |
R-81c | 2β,3α | 3.86 ± 0.2 | 5.62 ± 0.2 | 14.4 ± 1.3 | 1.4 | 3.7 | |
S-81d | 2β,3β | 1210 ± 33 | 424 ± 15 | 17300 ± 1800 | 0.3 | 14.3 | |
S-81e | 2α,3β | 27.6 ± 2.4 | 55.8 ± 5.73 | 1690 ± 150 | 2.0 | 61.2 | |
S-81f | 2β,3α | 407 ± 33 | 19 ± 1.8 | 1990 ± 176 | 0.05 | 4.9 |
N-replaced (S,O,C)
[edit]The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.
Compound | X | 2 Group | config | 8 | DA | 5-HT | NE |
Tropoxane | Cl,Cl | CO2Me | (racemic) β,β | O | 3.3 | 6.5 | No data |
O-4210[36] | p-F | 3-methyl-5-isoxazole | β,β | S | 7.0 | >1000 | No data |
8-oxa bridgehead replacements
[edit]Structure | Compound # (S. Singh) | Para- (meta-) | DAT (IC50 nM) displacement of [H3]WIN 35428 | 5-HTT (IC50 nM) [H3]Citalopram | Selectivity 5-HTT/DAT |
---|---|---|---|---|---|
R/S-90a | H | >1000 | >1000 | - | |
R/S-90b | F | 546 | 2580 | 4.7 | |
R/S-90c | Cl | 10 | 107 | 10.7 | |
R/S-90d | Br | 22 | 30 | 1.4 | |
R/S-90e | I | 7 | 12 | 1.7 | |
R/S-90f | 3,4-Cl2 | 3.35 | 6.52 | 1.9 | |
R-90g | 3,4-Cl2 | 3.27 | 4.67 | 1.4 | |
S-90h | 3,4-Cl2 | 47 | 58 | 1.2 | |
R/S-91a | H | 1990 | 11440 | 5.7 | |
R/S-91b | F | >1000 | >10000 | - | |
R/S-91c | Cl | 28.5 | 816 | 28.6 | |
R/S-91d | Br | 9 | 276 | 30.7 | |
R/S-91e | I | 42 | 72 | 1.7 | |
R/S-91f | 3,4-Cl2 | 3.08 | 64.5 | 20.9 | |
R-91g | 3,4-Cl2 | 2.34 | 31 | 13.2 | |
S-91h | 3,4-Cl2 | 56 | 2860 | 51.1 |
8-carba bridgehead replacements
[edit]Structure | Compound # (S. Singh) | DAT (IC50 nM) displacement of [H3]WIN 35428 | 5-HTT (IC50 nM) [H3]Citalopram | Selectivity 5-HTT/DAT |
---|---|---|---|---|
R/S-98a | 7.1 ± 1.7 | 5160 ± 580 | 726 | |
R/S-98b | 9.6 ± 1.8 | 33.4 ± 0.6 | 3.5 | |
R/S-98c | 14.3 ± 1.1 | 180 ± 65 | 12.6 |
N-alkyl
[edit]Compound | X | 2 Group | config | 8 | DAT | SERT | NET |
---|---|---|---|---|---|---|---|
FP-β-CPPIT | Cl | 3′-phenylisoxazol-5′-yl | β,β | NCH2CH2CH2F | - | - | - |
FE-β-CPPIT | Cl | (3′-phenylisoxazol-5′-yl) | β,β | NCH2CH2F | - | - | - |
Altropane (IACFT) | F | CO2Me | β,β | NCH2CH=CHF | - | - | - |
FECNT[37] | I | CO2Me | β,β | NCH2CH2F | - | - | - |
RTI-310 U.S. patent 5,736,123 | I | CO2Me | β,β | N-Prn | 1.17 | - | - |
RTI-311 | I | CO2Me | β,β | NCH2CH=CH2 | 1.79 | - | - |
RTI-312 U.S. patent 5,736,123 | I | CO2Me | β,β | NBun | 0.76 | - | - |
RTI-313 U.S. patent 5,736,123 | I | CO2Me | β,β | NCH2CH2CH2F | 1.67 | - | - |
Ioflupane (FP-CIT) | 123I | CO2Me | β,β | NCH2CH2CH2F | - | - | - |
PE2I[37] | Me | CO2Me | β,β | NCH2CH=CHI | - | - | - |
RTI-251 | Cl | CO2Me | β,β | NCH2CO2Et | 1.93 | 10.1 | 114 |
RTI-252 | Cl | CO2Me | β,β | NCH2CH2CO2Et | 2.56 | 35.2 | 125 |
RTI-242 | Cl | β,β (bridged) -C(O)CH(CO2Me)CH2N | 7.67 | 227 | 510 |
Bi- and tri-cyclic aza compounds and their uses.[38][39]
Structure | Short Name (S. Singh) | Nitrogen side-chain (N8) | DAT [3H]GBR 12935 Ki (nM) | 5-HTT [3H]Paroxetine Ki (nM) | NET [3H]Nisoxetine Ki (nM) | Selectivity 5-HTT/DAT | Selectivity NET/DAT |
---|---|---|---|---|---|---|---|
Cocaine | H | 350 ± 80 | >10000 | >30000 | >28.6 | - | |
GBR 12909 | - | 0.06 ± 0.02 | 52.8 ± 4.4 | >20000 | 880 | - | |
WIN 35428 11b | H | 14.7 ± 2.9 | 181 ± 21 | 635 ± 110 | 12.3 | 43.2 | |
RTI-55 11e | H | 1.40 ± 0.20 | 0.46 ± 0.06 | 2.80 ± 0.40 | 0.3 | 2 | |
82a | CH2CH=CH2 | 22.6 ± 2.9ɑ | - | - | - | - | |
82b | CH2CH2CH3 | 43.0 ± 17.7ɑ | - | - | - | - | |
82c | CH2C6H5 | 58.9 ± 1.65b | 1073c | - | 18.2 | - | |
82d | (CH2)3C6H5 | 1.4 ± 0.2b | 133 ± 7c | - | 95.0 | - | |
82e | (CH2)5C6H5 | 3.4 ± 0.83b | 49.9 ± 10.2c | - | 14.7 | - | |
83a | CH2CH2CH2F | 1.20 ± 0.29 | 48.7 ± 8.4 | 10000 | 40.6 | 8333 | |
83b | CH2CH2F | 4.40 ± 0.35 | 21.7 ± 8.3 | >10000 | 4.9 | - | |
84a | CH2CH2CH2F | 3.50 ± 0.39 | 0.110 ± 0.02 | 63.0 ± 4.0 | 0.03 | 18 | |
84b | CH2CH2F | 4.00 ± 0.73 | 0.140 ± 0.02 | 93.0 ± 17.0 | 0.03 | 23.2 | |
84c | CH2CHF2 | 15.1 ± 3.7 | 9.6 ± 1.5 | >5000 | 0.6 | - | |
84d | CH2CH2CH2Cl | 3.10 ± 0.57 | 0.32 ± 0.06 | 96.0 ± 29.0 | 0.1 | 31.0 | |
84e | CH2CH2CH2Br | 2.56 ± 0.57 | 0.35 ± 0.08 | 164 ± 47 | 0.1 | 64.1 | |
84f | CH2CH2CH2I | 38.9 ± 6.3 | 8.84 ± 0.53 | 5000 | 0.2 | 128 | |
84g | CH2...methylcyclopropane | 4.30 ± 0.87 | 1.30 ± 0.25 | 198 ± 9.6 | 0.3 | 46.0 | |
84h | CH2CH2CH2OH | 5.39 ± 0.21 | 2.50 ± 0.20 | 217 ± 19 | 0.5 | 40.2 | |
84i | CH2CH2(OCH3)2 | 6.80 ± 1.10 | 1.69 ± 0.09 | 110 ± 7.7 | 0.2 | 16.2 | |
84j | CH2CO2CH3 | 11.9 ± 1.4 | 0.81 ± 0.10 | 29.1 ± 1.0 | 0.07 | 2.4 | |
84k | CH2CON(CH3)2 | 12.2 ± 3.8 | 6.40 ± 1.70 | 522 ± 145 | 0.5 | 42.8 | |
84l | CH2CH2CH2OMs | 36.3 ± 2.1 | 17.3 ± 1.2 | 5000 | 0.5 | 138 | |
84m | COCH(CH3)2 | 2100 ± 140 | 102 ± 23 | >10000 | 0.05 | - | |
84n | (CH2)2Pht | 4.23 ± 0.48 | 0.84 ± 0.02 | 441 ± 66.0 | 0.2 | 104 | |
84o | (CH2)3Pht | 9.10 ± 1.10 | 0.59 ± 0.07 | 74.0 ± 11.6 | 0.06 | 8.1 | |
84p | (CH2)4Pht | 2.38 ± 0.22 | 0.21 ± 0.02 | 190 ± 18.0 | 0.09 | 79.8 | |
84q | (CH2)5Pht | 2.40 ± 0.17 | 0.34 ± 0.03 | 60.0 ± 3.10 | 0.1 | 25.0 | |
84r | (CH2)8Pht | 2.98 ± 0.30 | 0.20 ± 0.02 | 75.0 ± 3.6 | 0.07 | 25.2 | |
84sd | CH2CH=CH-CH3 | 15 ± 1 | 75 ± 5 | 400 ± 80 | 5.0 | 26.7 | |
84td | CH2C(Br)=CH2 | 30 ± 5 | 200 ± 40 | >1000 | 6.7 | - | |
84ud | CH2CH=CH2I(E) | 30 ± 5 | 960 ± 60 | 295 ± 33 | 32.0 | 9.8 | |