Pyrrolidinyl-benzamide誘導体の抗ドパミン作用
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Twenty-seven pyrrolidinyl-benzamides in which substituents at 4 (R_1) and 5 (R_2) positions on benzoyl moiety and at nitrogen of pyrrolidine rings (3-pyrrolidinyl, cis-2-methylpyrrolidin-3-yl and 2-pyrrolidinylmethyl types) varied, including YM-09151-2 and sulpiride, were evaluated for their activities in inhibiting apomorphine-induced stereotypy and conditioned avoidance response and causing catalepsy in mice and rats by subcutaneous (s.c.) and intracerebroventricular (i.c.v.) administration. 1) In variation of R_1 substituents on cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxybenzamides, s.c. activities in inhibition of stereotypy and avoidance and induction of catalepsy increased in the order of CH_3NH (V) > (CH_3)_2N (VI) ≥NH_2 (IV) > H (III). After i.c.v. injection, however, the rank of potencies was CH_3NH > NH_2 ≥ (CH_3)_2N. Monomethylation of the p-amino substituent on benzoyl moiety was also found to enhance s.c. activities in other benzamides (II > I, VIII > VII, XI > X, XIV > XIII, XXIII > XXII). 2) Chlorine as R_2 substituents was more favourable than a methylsulfonyl group for intensifying anti-dopaminergic activity after s.c. administration (IV > VII, V > VIII, XIII > XV, XIX > XXI). Compounds IV and V exhibited more potent anti-dopaminergic activity than VII and VIII, respectively, both by s.c. and i.c.v. routes. In contrast, compound IX and sulpiride bearing R_2=NH_2SO_2 caused anti-dopaminergic activity only after i.c.v. injection. 3) Introduction of a benzyl group at nitrogen on the pyrrolidin ring instead of an ethyl group enhanced anti-dopaminergic activity by s.c. injection. 4) Compounds IV-VIII were more potent in inhibiting stereotypy than in inducing catalepsy after i.c.v. administration, whereas IX and sulpiride were less potent in antistereotypic activity. These results indicate that the introduction of monomethyl-amino, chlorine and benzyl groups at 4 and 5 positions on benzoyl moiety and at nitrogen of pyrrolidine ring, respectively, provides for the optimum anti-dopaminergic activity of pyrrolidinyl-benzamides. In addition, a sulfamoyl substituent is not suitable for the penetration of compounds into the brain.
- 公益社団法人日本薬学会の論文
- 1987-09-25
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関連論文
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- Pyrrolidinyl-benzamide誘導体の抗ドパミン作用
- ド-パミン受容体 (生理活性アミンと生体制御--受容体・生理・病理) -- (生理活性アミンの受容体)