CoMFA Study of Novel Phenyl Ring-Substituted 3α-(Diphenylmethoxy)tropane Analogues at the Dopamine Transporter

Publisher Website
Google Scholar
Abstract
A series of phenyl ring-substituted analogues of 3α-(diphenylmethoxy)tropane (benztropine) has been prepared as novel probes for the dopamine transporter. Cross-validated comparative molecular field analysis (CoMFA) models of the binding domain on the dopamine transporter were constructed using 37 geometry-optimized structures of these compounds and their corresponding binding affinities (Ki values) for the displacement of [3H]WIN 35,428 or potency of [3H]dopamine uptake inhibition (IC50 values) in rat caudate putamen tissue. The most predictive model (q2 = 0.78) correlated the steric component of CoMFA to the dependent variable of [3H]WIN 35,428 binding affinities. A novel series of seven phenyl ring-substituted analogues of 3α-(diphenylmethoxy)tropane was prepared, and our best molecular model was used to accurately predict their binding affinities. This study is the first to provide a CoMFA model for this class of dopamine uptake inhibitors. This model represents an advancement in the design of novel dopamine transporter ligands, based on 3α-(diphenylmethoxy)tropane, and further substantiates structure−activity relationships that have previously been proposed for this class of compounds. This CoMFA model can now be used to predict the binding affinities of novel 3α-(diphenylmethoxy)tropane analogues at the dopamine transporter and will be useful in the design of molecular probes within this class of dopamine uptake inhibitors.

This publication has 23 references indexed in Scilit: