DOPAMINE D-3 AND D-4 RECEPTOR ANTAGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF -4-[(CYCLOPROPYLCARBONYL)AMINO]-2-METHOXYBENZAMIDE (YM-43611) AND RELATED-COMPOUNDS())

In this study, we synthesized a series of (S)-N-(3-pyrrolidinyl)benzam ide derivatives, 1, 2a-d, 5a-1, and 7, and their enantiomers, (R)-1 an d (R)-5c-e, and evaluated their binding affinity for cloned dopamine D -2, D-3, and D-4 receptors and their inhibitory activity against apomo rphine-induced climbing behavior in mice. The results indicate that D- 2, D-3, and D-4 receptors have different bulk tolerance (D-4 > D-3 > D -2) for the substituent of the 4-amino group (R(1)) on the benzamide n uclei and that cyclopropyl-, cyclobutyl-, and cyclopentylcarbonyl grou ps likely possess adequate bulkiness with respect to D-3 and D-4 affin ity and selectivity over D-2 receptors in this series. The results als o suggested that the N-substituent (R(2)) On the pyrrolidin-3-yl group performs an important role in expressing affinity for D-2, D-3, and D -4 receptors and selectivity among the respective subtypes. One of the compounds, -4-[(cyclopropylcarbonyl)amino]-2-methoxybenzamide (5c) (Y M-43611), showed high affinity for D-3 and D-4 receptors (K-i values o f 21 and 2.1 nM, respectively) with 110-fold D-4 selectivity and 10-fo ld D-3 preference over D-2 receptors and weak or negligible affinity f or representative neurotransmitter receptors. Compound 5c displayed po tent antipsychotic activity in inhibiting apomorphine-induced climbing behavior in mice (ED(50) value, 0.32 mg/kg sc).