Ringdahl B, Resul B, Jenden D J, Dahlbom R
Eur J Pharmacol. 1982 Nov 5;85(1):79-83. doi: 10.1016/0014-2999(82)90426-5.
A series of structural analogues of the potent oxotremorine-like agent N-(4-pyrrolidino-2-butynyl)-N-methyl-acetamide (1) was investigated for muscarinic activity in the isolated guinea pig ileum. Substitution of larger alkyl groups for the acetyl methyl group of 1 results in an attenuation of muscarinic potency. The observation that the agonist N-(4-dimethylamino-2-butynyl)-N-methylpropionamide (6) has a dissociation constant (KA = 5.1 X 10(-5) M), estimated after elimination of spare receptors with dibenamine, similar to that of the antagonist N-(4-dimethylamino-2-butynyl)-N-methyl-2,2-dimethylpropionamide (11) suggests that the decrease in muscarinic agonist activity with increasing substitution is due mainly to a loss of efficacy. The N-methyl group of 1 is essential for muscarinic activity since its replacement by a hydrogen atom or an ethyl group yields antagonists.
研究了一系列强效类氧代震颤素药物N-(4-吡咯烷基-2-丁炔基)-N-甲基乙酰胺(1)的结构类似物在离体豚鼠回肠中的毒蕈碱活性。用较大的烷基取代1的乙酰甲基会导致毒蕈碱效力减弱。激动剂N-(4-二甲基氨基-2-丁炔基)-N-甲基丙酰胺(6)在用双苄胺消除备用受体后估计的解离常数(KA = 5.1×10(-5)M)与拮抗剂N-(4-二甲基氨基-2-丁炔基)-N-甲基-2,2-二甲基丙酰胺(11)相似，这表明随着取代增加毒蕈碱激动剂活性的降低主要是由于效力丧失。1的N-甲基对于毒蕈碱活性至关重要，因为用氢原子或乙基取代它会产生拮抗剂。
