Lead Optimization for Discovery of Potent and Selective Dopamine Receptor D₄ Antagonist

Abstract

Stimulant dependence is a prolonged relapsing condition that can be exhibited by reinstatement animal models. Dopamine D₄ receptor antagonists are shown to interrupt drug seeking when induced by stress cues or introduction of the stimulant meaning the D₄ receptor is a viable target for stimulant abuse, specifically cocaine dependence. Further evidence implicating D₄ receptor is due to greater expression of D₄ mRNA in regions of the forebrain associated with cocaine dependence. A selective and potent D₄ antagonist, ML398, was shown to reverse cocaine-induced hyperlocomotion; issues surrounding metabolic stability and clearance of this molecule led to optimization efforts. With ML398 as a starting point, scaffolds were synthesized with substituted phenyl and pyridinyl groups with ether linkages to the morpholine core and rapidly analogued. The morpholine core was altered to a difluoropiperidine to combat issues with pharmacokinetic properties. Various difluoropiperidine scaffolds were prepared with electron donating and withdrawing groups around the phenyl ring and analogued. Withdrawing group substitution around the phenyl ring of the difluoropiperidine is well tolerated.