SYNTHESIS, LIGAND-BINDING, AND QSAR (COMFA AND CLASSICAL) STUDY OF 3-BETA-(3'-SUBSTITUTED PHENYL), 3-BETA-(4'-SUBSTITUTED PHENYL), AND 3-BETA-(3',4'-DISUBSTITUTED PHENYL)TROPANE-2-BETA-CARBOXYLIC ACID METHYL-ESTERS

Several new 3 beta-(4'-substituted phenyl)-, 3 beta-(3'-substituted ph enyl)-, and 3 beta-(3',4'-disubstituted phenyl)tropane-2 beta-carboxyl ic acid methyl esters were prepared and assayed for inhibition of [H-3 ]WIN 35,428 binding to the dopamine transporter. The 3 beta-(3',4'-dic hloro) and 3 beta-(4'-chloro-3'-methyl) analogues (2w and 2y; RTI-111 and RTI-112, respectively) with IC50 values of 0.79 and 0.81 nM showed the highest affinity. The contributions of quantitative structure-act ivity relationship (QSAR) models derived from the classical and compar ative molecular field analysis (CoMFA) approaches to rational drug des ign were examined. CoMFA models were derived using steric and electros tatic potentials with SYBYL default values while the classical models were derived from pi and MR parameters. Using a 12-compound training s et, both models were used for predicting the binding affinity of compo unds both inside and outside the training set. The CoMFA study provide d new insight into the steric and electrostatic factors influencing bi nding to the DA transporter and provided additional support for our or iginal finding that CoMFA is useful in predicting and designing new co mpounds for study. The classical QSAR models, which were easier to obt ain, suggest that the distribution property (pi) of the compounds is a n important factor. Overall, the SAR, CoMFA, and conventional QSAR stu dies elaborated some features of the cocaine binding site pharmacophor e and provided useful predictive information.