The dopamine D4receptor (D4R), a G protein-coupled receptor, is predominantly expressed in the prefrontal cortex in which it plays an important role in cognition, attention, and decision making. Studies have indicated D4R-selective ligands as a promising medication development to treat neuropsychiatric conditions such as substance use disorders (SUD). D4R ligands have been shown to alter cognition and behavior in animal models of drug addiction. A better understanding of D4R-mediated signaling is essential to treating D4R-associated disorders, including SUD. Despite its clinical importance, there are no currently approved medications that target the D4R for cocaine abuse disorder treatment. The present study focuses on the design of D4R ligands based on benzo[d]thiazole scaffold template as the initial parent compound. Metabolic stability in rat and human liver microsomes, followed by in vivopharmacokinetics analyses were performed.We identified several compounds with high D4R binding affinity and subtype selectivity (Ki ≤ 6.87 nM and &gt;91-fold vs. other D2-like receptors (D2R, D3R)). Compound were found to be selective D4R antagonists in functional β-arrestin recruitment and cAMP inhibition assays. Based on the analysis profiles, lead compounds were selected for in vitrometabolic stability in rats and human liver microsomes of which some displayed acceptable stability profiles. Of these, CAB-01-019 was selected for in vivopharmacokinetics in rats where it displayed excellent brain penetration with AUCbrain/plasma&gt;3.These novel ligands display high binding affinity and subtype selectivity for D4R with advantageous pharmacokinetic profiles. Further development of these compounds may provide insights to targeted drug discovery leading to a better understanding of the role of D4Rs in neuropsychiatric disorders such as SUD.

Benzothiazole analogues as dopamine D4 receptor selective ligands to treat substance use disorder

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ACS Fall 2022

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