(-)-3 beta-Substituted ecgonine methyl esters as inhibitors for cocaine binding and dopamine uptake

Journal of Medicinal Chemistry
S F LieskeJ Wright

Abstract

Ten 3 beta-ecgonine analogues were synthesized and characterized by 1H and 13C NMR, MS, and elemental analysis. The compounds were synthesized as (-)-stereoisomers from (-)-cocaine. These compounds were assessed for their ability to inhibit [3H]cocaine binding to rat striatal tissue and to inhibit [3H]DA uptake into rat striatal synaptosomes. In this series of compounds, the length of the spacer between the aryl group and the tropane skeleton ranged from 1 to 4 bond distances, and conformational flexibility of the linkage and orientation of the aryl ring system were controlled by various types of linkages. The most potent of the analogues was methyl-(1R-2-exo-3-exo)-8-methyl-3-(beta-styrenyl)-8-azabicyclo[3. 2.1] octane-2-carboxylate. One of the less potent compounds was found to inhibit [3H]cocaine binding and [3H]DA uptake with significantly different IC50 values, in contrast to 14 other 3 beta-substituted analogues. Molecular modeling and CoMFA analysis were used to obtain a rigorous structure-function relationship for the studied compounds. The results showed that the potencies of these 3 beta-substituted ecgonine methyl esters were dominated by steric effects and were acutely sensitive to the distance between the aryl ring...Continue Reading

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Citations

Jul 21, 2006·Journal of Computer-aided Molecular Design·Kathleen M Gilbert, Carol A Venanzi
Nov 13, 2003·European Journal of Pharmacology·George R Uhl, Zhicheng Lin
Aug 22, 2001·Bioorganic & Medicinal Chemistry Letters·P A PetukhovA P Kozikowski
Aug 6, 2002·Bioorganic & Medicinal Chemistry Letters·Amy L BradleyMark L Trudell
Mar 12, 2002·Bioorganic & Medicinal Chemistry·Michael AppellJudith L Flippen-Anderson
Mar 5, 2003·Bioorganic & Medicinal Chemistry·Sukumar SakamuriShaomeng Wang
Jan 16, 2002·Journal of Biomolecular Structure & Dynamics·G IzaguirreA MacKerell
Oct 8, 2003·Movement Disorders : Official Journal of the Movement Disorder Society·George R Uhl
May 4, 2005·Journal of Computer-aided Molecular Design·Kathleen M GilbertCarol A Venanzi
Mar 12, 2019·Integrative Biology : Quantitative Biosciences From Nano to Macro·Duo ZhangLinxin Chen
Feb 14, 2006·Journal of Computational Chemistry·Anna FiorentinoCarol A Venanzi
Feb 19, 2002·Chemical Reviews·Christopher J. Cramer, Donald G. Truhlar
Oct 16, 2012·ACS Medicinal Chemistry Letters·David J LapinskyHoward M Deutsch
Feb 24, 2007·Biochemistry·Yuenmu ChenArnold E Ruoho
Mar 31, 2005·Journal of the American Chemical Society·Stefan BoreschAlexander D MacKerell
Sep 6, 2002·Journal of Medicinal Chemistry·William J HoulihanTheresa A Kopajtic
Sep 6, 2002·Journal of Medicinal Chemistry·Santosh S KulkarniWilliam J Houlihan

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