While dopaminergic pathways have been clearly implicated in the reinforcing aspects of reward, the precise role of the dopamine receptor subtypes in motivation for drug seeking behaviors, reinstatement, drug craving and relapse remains unclear. The hypothesis for this application is that arylamide phenylpiperazine analogs, that bind with high affinity at D3 dopamine receptors and varying D3 vs. D2 receptor selectivity, can be used safely for the treatment of cocaine abuse in the context of a drug rehabilitation program. Based upon the information gained from our previous studies, we propose new synthetic strategies to identify compounds with the desired pharmacological profiles and pharmacokinetic (PK) properties appropriate for the treatment of cocaine abuse in humans by 1) modifying the orthosteric pharmacophore (phenylpiperazine moiety) and 2) integrating information obtained from binding and functional studies, as well as findings from adsorption, distribution, metabolic, elimination (ADME) studies and PK analysis into the synthetic design. Select compounds will then be tested in rats to evaluate their ability to attenuate cocaine-associated behaviors. This research has the potential to lead to a new treatment strategy for cocaine dependence and psychostimulant abuse-related behaviors.
Aim 1. Synthesis of novel D3 receptor selective compound with increased efficacy. We propose to modify the phenylpiperazine orthosteric pharmacophore by synthesizing panels of novel arylamide homopiperazine, imidazolidine, aza-tropane and aza-granatane analogs.
Aim 2. Evaluation of binding and functional selectivity. The affinity of analogs described in Aim 1 will be determined at D1 dopamine, D2-like (D2, D3 and D4) dopamine, sigma 1 and 2 receptors using radioligand binding techniques. In addition, the intrinsic efficacy of our novel compounds will be evaluated using multiple in vitro functional assays including, a) adenylyl cyclase inhibition, b) mitogenesis c) MAPK/pERK pathway activation and d) -arrestin binding. Compounds will also be tested in vivo for cFos activation, effects on spontaneous locomotion and effects on rotarod performance.
Aim 3. Evaluation of selected compounds for ADME and pharmacokinetic properties. Based upon binding and functional selectivity profile (Aim 2), a select panel of D3 receptor selective compounds will be evaluated using a battery of in vitro ADME and in vivo PK profiling assays.
Aim 4. Evaluate the effects of the newly synthesized compounds on cocaine reinforcement, motivation and motor function. A select panel of novel compounds (Aims 1-3) will be evaluated for their effects on cocaine self-administration under low and progressive ratio reinforcement schedules and on reinstatement of extinguished cocaine seeking behavior.
This application details a strategy for the synthesis of novel D3 dopamine receptor selective arylamide phenylpiperazine analogs, which will be evaluated for binding affinity, intrinsic efficacy and functional selectivity. Based upon the results of binding nd functional assays, select compounds will be evaluated using a battery of in vitro absorption, distribution, metabolism and excretion and in vivo pharmacokinetic assays to identify compounds with the greatest in vivo half life. The most promising and pharmacologically unique compounds will then be evaluated for their effects on cocaine self-administration, drug seeking motivation and reinstatement of extinguished cocaine seeking behavior.
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