title: Muscarinic actions and receptor binding of the enantiomers of BM 130, an alkylating analog of oxotremorine.
abstract: The enantiomers of the oxotremorine analog N-[4-(2-chloromethylpyrrolidine)-2-butynyl]-2-pyrrolidone (BM 130) were synthesized. The LD50 values of (+)- and (-)-BM 130 in mice (i.v.) were 10.4 +/- 1.4 and 13.5 +/- 1.9 mumol/kg, respectively. Atropine and N-methylatropine poorly protected against the lethal effects, suggesting that they were nonmuscarinic in nature. When administered i.v. to mice, (+)- and (-)-BM 130 were equipotent in producing peripheral and central muscarinic effects. ED50 values were 1.3 to 1.4, 2.8 to 3.2 and 0.20 to 0.26 mumol/kg, respectively, for salivation, tremor and analgesia (tail-flick assay). After i.p. injection, tremor was not observed and analgesic potency was reduced more than 10-fold compared to the i.v. route. The aziridinium ions [(+)- and (-)-BM 130A], formed by spontaneous cyclization of (+)- and (-)-BM 130, were virtually equipotent in eliciting contractions of the isolated guinea pig ileum and in causing salivation in mice. Their LD50 values in mice (i.v.) were 1.1 +/- 0.2 and 2.1 +/- 0.3 mumol/kg, respectively. The enantiomers of BM 130A had similar affinity for muscarinic receptors in the rat cerebral cortex as measured by competitive inhibition of (-)-[3H]N-methylscopolamine binding at 0 degrees C. The rate constants for alkylation of muscarinic receptors, obtained at 37 degrees C by measuring the decline in (-)-[3H]-3-quinuclidinyl benzilate binding to cortical homogenates that had been treated with various concentrations of (+)- and (-)-BM 130A for 20, 45 or 90 min, differed significantly for the two enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Los Angeles.
authors.forename: B
authors.initials: B
authors.lastname: Ringdahl
authors.forename: E D
authors.initials: ED
authors.lastname: Katz
authors.forename: M
authors.initials: M
authors.lastname: Roch
authors.forename: D J
authors.initials: DJ
authors.lastname: Jenden
mesh_terms: D000478:Alkylation; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010095:Oxotremorine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D013237:Stereoisomerism; D014202:Tremor / Q000139:chemically induced
chemical_list: D011976:Receptors, Muscarinic; D010095:Oxotremorine; C043039:N-(4-(2-chloromethylpyrrolidino)-2-butynyl)-2-pyrrolidone