Dopamine D₃ and D₄ Receptor Antagonists:  Synthesis and Structure−Activity Relationships of (S)-(+)-N-(1-Benzyl-3-pyrrolidinyl)-5-chloro-4- [(cyclopropylcarbonyl)amino]-2-methoxybenzamide (YM-43611) and Related Compounds

In this study, we synthesized a series of (S)-N-(3-pyrrolidinyl)benzamide derivatives, 1, 2a−d, 5a−l, and 7, and their enantiomers, (R)-1 and (R)-5c−e, and evaluated their binding affinity for cloned dopamine D₂, D₃, and D₄ receptors and their inhibitory activity against apomorphine-induced climbing behavior in mice. The results indicate that D₂, D₃, and D₄ receptors have different bulk tolerance (D₄ > D₃ > D₂) for the substituent of the 4-amino group (R) on the benzamide nuclei and that cyclopropyl-, cyclobutyl-, and cyclopentylcarbonyl groups likely possess adequate bulkiness with respect to D₃ and D₄ affinity and selectivity over D₂ receptors in this series. The results also suggested that the N-substituent (R) on the pyrrolidin-3-yl group performs an important role in expressing affinity for D₂, D₃, and D₄ receptors and selectivity among the respective subtypes. One of the compounds, (S)-(+)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-[(cyclopropylcarbonyl)amino]-2-methoxybenzamide (5c) (YM-43611), showed high affinity for D₃ and D₄ receptors (K_i values of 21 and 2.1 nM, respectively) with 110-fold D₄ selectivity and 10-fold D₃ preference over D₂ receptors and weak or negligible affinity for representative neurotransmitter receptors. Compound 5c displayed potent antipsychotic activity in inhibiting apomorphine-induced climbing behavior in mice (ED₅₀ value, 0.32 mg/kg sc).