The neurotransmitter dopamine signals through G protein-coupled receptors that regulate a variety of neurophysiological functions, including movement, emotional regulation, motivation, and cognition. The dopamine D4 receptor (D4R) plays an important role in cognition, attention, and decision making. Studies have indicated that the D4R is a promising therapeutic target for the treatment of neuropsychiatric conditions such as substance use disorders (SUD). 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 selectively target the D4R for cocaine use disorder. Herein we report the development and structure-activity relationships of a novel class of highly D4R-selective ligands based on a benzo[d]thiazole scaffold template. The compounds were designed and synthesized following computational modeling predicting favorable interactions. A library of eighteen compounds were synthesized with varied substitutions on the pyrimidinylpiperidinyl (PP) ring and/or the benzothiazole moieties. In vitro binding affinities of the compounds were determined via [3H]N-methylspiperone radioligand binding using membranes prepared from HEK293 cells expressing dopamine D2-like receptors (D2R, D3R, or D4R). The ligands were also studied in β-arrestin recruitment and cAMP inhibition assays for their effects on D2R-like function. We further performed in vitro and in vivo pharmacokinetic analyses with selected compounds. We identified several compounds with nanomolar D4R binding affinity and excellent D2-like subtype selectivity (&gt;91-fold vs. D2R and D3R). Several compounds were selective D4R antagonists in functional β-arrestin recruitment and cAMP inhibition assays. Based on the analysis profiles, lead compounds were selected for in vitro metabolic stability in rats and human liver microsomes of which some displayed moderate stability profiles. One of the lead candidates was selected for in vivo pharmacokinetics assessment 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

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.