Characterization of the transport, metabolism, and pharmacokinetics of the dopamine D3 receptor selective fluorenyl-and 2-pyridylphenyl amides developed for treatment of psychostimulant abuse JPET #165084 2 RUNNING TITLE PAGE a) Running Title: Characteriz

ABSTRACT The recent discovery of novel high affinity and selective dopamine D3 receptor (DA D3R) antagonists and partial agonists has provided tools with which to further elucidate the role DA D3R plays in substance abuse. The present study was conducted to evaluate the transport, metabolism, pharmacokinetics and brain uptake of the DA D3R selective fluorenyl amides, NGB 2904 and JJC 4-077, and the 2-pyridylphenyl amides, CJB 090 and PG 01037, all of which have been studied in animal models of psychostimulant abuse. Additional screening with a panel of human and rat Supersomes was performed for NGB 2904 and PG 01037. Drug stimulated ATPase activation assays and bidirectional transport and efflux assays were used to test for substrate specificity of NGB 2904 and PG 01037 for human and rat efflux transporters. All compounds exhibited moderate elimination half-lives, ranging from 1.49-3.27 hrs, and large volumes of distribution (5.95-14.19 l/kg). The brain-to-plasma ratios ranged from 2.93-11.81 and were higher than that previously reported for cocaine. Brain exposure levels of NGB 2904 and PG 01037 were significantly reduced following i.p. administration compared to i.v. administration. The metabolism of these compounds was mediated primarily by CYP3A subfamilies. PG 01037 was a P-gp transported substrate. Higher doses of these compounds are often required for in vivo action suggesting decreased bioavailability via extravascular administration which may be attributed to high drug efflux and hepatic metabolism. These studies provide important preclinical information for optimization of next generation D3R selective agents for the treatment of drug addiction