ML-398

Pharmacological targeting of the dopamine D₄ receptor (D₄R)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D₄R. We identified several compounds with high D₄R binding affinity (K_i ≤ 6.9 nM) and >91-fold selectivity over other D₂-like receptors (D₂R, D₃R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D₄R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUC_brain/plasma > 3). 16f (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D₄R-selective antagonists. Off-target antagonism of 5-HT_2A or 5-HT_2B may also contribute to these effects. Results with 16f support further efforts to target D₄R in SUD treatment.