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-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).
Ohmori
J
J
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Company Limited, Ibaraki, Japan.
Maeno
K
K
Hidaka
K
K
Nakato
K
K
Matsumoto
M
M
Tada
S
S
Hattori
H
H
Sakamoto
S
S
Tsukamoto
S
S
Usuda
S
S
Mase
T
T
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001549:Benzamides; C493593:DRD3 protein, human; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493594:Drd3 protein, mouse; C493595:Drd3 protein, rat; C493600:Drd4 protein, mouse; C493601:Drd4 protein, rat; C100801:N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-((cyclopropylcarbonyl)amino)-2-methoxybenzamide; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4