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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (DDNS)
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Shih, Ming L
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University of North Texas
Other Domestic Higher Education
Fort Worth
United States
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Reilly, Sean W; Griffin, Suzy; Taylor, Michelle et al. (2017) Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores. J Med Chem 60:9905-9910
Reilly, Sean W; Mach, Robert H (2016) Pd-Catalyzed Synthesis of Piperazine Scaffolds Under Aerobic and Solvent-Free Conditions. Org Lett :
Peng, Xin; Wang, Qi; Mishra, Yogesh et al. (2015) Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands. Bioorg Med Chem Lett 25:519-23
Neisewander, Janet L; Cheung, Timothy H C; Pentkowski, Nathan S (2014) Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development. Neuropharmacology 76 Pt B:301-19
Rangel-Barajas, Claudia; Malik, Maninder; Taylor, Michelle et al. (2014) Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand. J Neurochem 131:418-31
Li, Aixiao; Mishra, Yogesh; Malik, Maninder et al. (2013) Evaluation of N-phenyl homopiperazine analogs as potential dopamine D3 receptor selective ligands. Bioorg Med Chem 21:2988-98
Xu, Jinbin; Vangveravong, Suwanna; Li, Shihong et al. (2013) Positron emission tomography imaging of dopamine D2 receptors using a highly selective radiolabeled D2 receptor partial agonist. Neuroimage 71:168-74
Zorrilla, Eric P; Koob, George F (2013) Amygdalostriatal projections in the neurocircuitry for motivation: a neuroanatomical thread through the career of Ann Kelley. Neurosci Biobehav Rev 37:1932-45
Cheung, Timothy H C; Loriaux, Amy L; Weber, Suzanne M et al. (2013) Reduction of cocaine self-administration and D3 receptor-mediated behavior by two novel dopamine D3 receptor-selective partial agonists, OS-3-106 and WW-III-55. J Pharmacol Exp Ther 347:410-23
Sun, Jianjun; Kouranova, Evguenia; Cui, Xiaoxia et al. (2013) Regulation of dopamine presynaptic markers and receptors in the striatum of DJ-1 and Pink1 knockout rats. Neurosci Lett 557 Pt B:123-8

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