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

Stacey A. Lomenzo, Sari Izenwasser, Jonathan L. Katz, Phyllis D. Terry, Naijue Zhu, Cheryl L. Klein, Mark L. Trudell

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

A series of 6-alkyl-3β-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter (DAT). The in vitro affinity (K(i)) for the DAT of the 6-alkyl-3β-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 (K(i) = 33 nM) and surprisingly (+)-20a (K(i) = 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 3β-benzyl-2β- [(methoxycarbonyl)methyl]-6β-methyltropane (21b; K(i) = 57 nM) was the only 6-alkyl derivative to exhibit moderately potent activity. The 6β-isomer 21b was 4-fold more potent than the 6α-isomer 19b (K(i) = 211 nM) and was nearly equipotent with (-)-19a and (+)-20a as well as with cocaine and WIN 35,065- 2. The results of this study further demonstrate the steric constraints associated with the C(6)-C(7) methylene bridge of the tropane ring system for molecular recognition of cocaine analogues at the cocaine binding site(s) on the DAT.

Original languageEnglish (US)
Pages (from-to)4406-4414
Number of pages9
JournalJournal of Medicinal Chemistry
Volume40
Issue number26
DOIs
StatePublished - Dec 1 1997
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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