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

J Med Chem. 1996 Jul 5;39(14):2764-72. doi: 10.1021/jm9601720.

Abstract

In this study, we synthesized a series of (S)-N-(3-pyrrolidinyl)benzamide derivatives, 1, 2a-d, 5a-1, 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 (R1) 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 (R2) 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 (Ki 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).

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • CHO Cells
  • Cricetinae
  • Dopamine Antagonists / chemical synthesis*
  • Dopamine Antagonists / pharmacology
  • Dopamine D2 Receptor Antagonists*
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Motor Activity / drug effects
  • Rats
  • Receptors, Dopamine D3
  • Receptors, Dopamine D4
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Benzamides
  • DRD3 protein, human
  • DRD4 protein, human
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Drd3 protein, mouse
  • Drd3 protein, rat
  • Drd4 protein, mouse
  • Drd4 protein, rat
  • N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-((cyclopropylcarbonyl)amino)-2-methoxybenzamide
  • Receptors, Dopamine D3
  • Receptors, Dopamine D4