Synthesis, in vitro dopamine D₂ and D₃ receptor binding and quantitative structure-activity studies on substituted 2,3-dimethoxy-N-(1- benzyl-4-piperidinyl)benzamides and related compounds

In an effort to identify potent and selective antagonists at D₂-like dopamine receptors, a series of N-substituted 2,3-dimethoxy-N-(1-benzyl-4- piperidinyl)benzamides was prepared. The affinity of each compound for the rat D₂ and D₃ dopamine receptor has been determined in vitro using radioligand binding protocols with the baculovirus expression system. These studies were designed to explore the effects of steric and electronic modifications to the 4-piperidinyl portion of the benzamides on binding at both receptor sub-types. While the modifications led to compounds of high affinity (K(d) values equal to 1 to 3 nM) at both receptors, significant D₃ versus D₂ pharmacologic selectivity was not found. Quantitative structure- activity relationships that more precisely define structural modifications that maintain high-affinity are discussed for both the D₂ and D₃ receptor binding data.