The novel N‐substituted benztropine analog GA2‐50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse

GA2‐50 is a novel N‐substituted benztropine analog with improved potency and selectivity for the dopamine transporter. The pharmacokinetic and pharmacodynamic properties of GA2‐50 were characterized as a part of its preclinical evaluation as a substitute medication for cocaine abuse. In vitro transport and metabolism studies as well as pharmacokinetic studies in rats were conducted. Effect of GA2‐50 on the extracelluar nucleus accumbens (NAc) dopamine levels and on cocaine's induced dopamine elevation was evaluated using intracerebral microdialysis. GA2‐50 showed high transcellular permeability despite being a P‐glycoprotein substrate. GA2‐50 was a substrate of human CYP2D6, CYP2C19, CYP2E1, rat CYP2C11, CYP2D1, CYP3A1, and CYP1A2; with low intrinsic clearance values. In vivo, GA2‐50 showed high brain uptake (Ri ∼ 10), large volume of distribution (Vss = 37 L/kg), and long elimination half‐life (t½ = 19 h). GA2‐50 resulted in 1.6‐ and 2.7‐fold dopamine elevation at the 5 and 10 mg/kg i.v. doses. Dopamine elevation induced by GA2‐50 was significantly reduced, slower and longer lasting than previously observed for cocaine. GA2‐50 had no significant effect on cocaine's induced dopamine elevation upon simultaneous administration. Results from the present study indicate that GA2‐50 possesses several attributes sought after for a substitute medication for cocaine abuse. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci