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

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 (K i 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 (q 2 = 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.