Low-Efficacy Dopamine D4 Receptor Partial Agonists for Cocaine Addiction

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PROJECT SUMMARY/ABSTRACT Antagonism of the dopamine D4 receptor (D4R) signaling reduces drug-taking and -seeking behaviors, but may disrupt memory and cognitive processes. We hypothesize that low-efficacy partial agonists D4R may still attenuate drug-taking and -seeking behaviors with fewer disruptive side effects, representing a superior avenue for medications development for addiction. To test this hypothesis, we have developed a library of five new, structurally diverse D4R ligands with high D4R affinity, excellent D2-like subtype selectivity, and a broad range of receptor efficacies, including a high-efficacy partial agonist (1; CAB 02-017), two low-efficacy partial agonists (2, 3; CAB 02-011, CAB 03-015), and two full antagonists (4, 5; CAB 02-005, CAB 01-019). This proposal seeks to fully characterize 1-5 in comprehensive receptor screens, which will identify any important off-target effects of each drug, and in detailed pharmacokinetic analyses, including microsomal stability studies and in vivo timecourses of rat plasma and brain drug levels. These critical analyses will allow us to better design behavioral studies to test our central hypothesis and more completely interpret the results of the behavioral tests. Finally, we will evaluate the effects of 1-5 in rat models of cocaine addiction and relapse. 1-5 will be tested for their ability to shift cocaine dose-response curves in rats trained to self-administer cocaine, and their ability to attenuate relapse-like responding in cocaine-primed reinstatement tests. Preliminary data show that full antagonist 5 attenuates cocaine self-administration. The proposed Aims will allow us to test our central hypothesis, that low- efficacy D4R partial agonism can reduce cocaine-taking and -seeking behaviors. The full receptor selectivity and pharmacokinetic characterizations will not only enhance proper experimental design of our proposed behavioral studies, but will increase the utility of these compounds as broadly available research tools. Overall, this proposal leverages extensive in vitro data, and preliminary in vivo data, in support of the innovative and significant hypothesis that low-efficacy D4R partial agonists are a novel avenue for medications development for cocaine addiction.