Synthesis, structure, dopamine transporter affinity, and dopamine uptake inhibition of 6-alkyl-3-benzyl-2-[(methoxycarbonyl)methyl]tropane derivatives

Journal of Medicinal Chemistry
S A LomenzoM L Trudell

Abstract

A series of 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter (DAT). The in vitro affinity (Ki) for the DAT of the 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl) methyl]tropane analogues was determined by inhibition of [3H]WIN 35,428 in rat caudate putamen tissue. The inhibition of dopamine uptake (IC50) was also measured for selected compounds which demonstrated moderate affinity for the dopamine transporter. The unsubstituted enantiopure analogues (-)-19a (Ki = 33 nM) and surprisingly (+)-20a (Ki = 60 nM) were found to be almost equipotent with the high-affinity binding components of cocaine and WIN 35,065-2 and exhibited slightly more potent dopamine uptake inhibition than both cocaine and WIN 35,065-2. In general, substitution at the 6-position of racemic 19a and 20a with alkyl groups was found to result in decreased activity relative to increased chain length of the substituent. The 3 beta-benzyl-2 beta-[(methoxycarbonyl)methyl]-6 beta-methyltropane (21b; Ki = 57 nM) was the only 6-alkyl derivative to exhibit moderately potent activity. The 6 beta-isomer 21b was 4-fold more potent than the 6 alpha-isomer 19b (Ki = 211 nM...Continue Reading

References

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Citations

Jun 23, 1999·Drug Discovery Today·M P SmithA P Kozikowski
Jun 27, 2007·Nuclear Medicine and Biology·Birte DrewesHeinz H Coenen
Nov 18, 2004·Bioorganic & Medicinal Chemistry Letters·Peter C MeltzerBertha K Madras
Jun 15, 2017·The Journal of Organic Chemistry·Justin B DiccianniTianning Diao
Mar 19, 2004·Journal of Medicinal Chemistry·Lifen XuMark L Trudell
Feb 24, 2005·European Journal of Medicinal Chemistry·Anu J AiraksinenJouko Vepsäläinen

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