title: Effects of an alkylating derivative of oxotremorine (BM 123A) on heart rate, muscarinic receptors and adenylate cyclase activity in the rabbit myocardium.
abstract: The effects of the aziridinium ion (BM 123A) of a 2-chloroethylamine derivative of oxotremorine, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123), on heart rate, muscarinic receptor binding properties and adenylate cyclase activity were investigated in the rabbit myocardium. BM 123A was a potent inhibitor of heart rate in spontaneously beating rabbit hearts. Perfusion of hearts with BM 123A for 30 min caused a lack of sensitivity of the heart to the muscarinic agonist oxotremorine-M and an 80% alkylation of muscarinic receptors as measured by the reduction in the binding capacity of N-[3H]methylscopolamine. Alkylation of muscarinic receptors in the heart with BM 123A had no significant effect on adenylate cyclase activity by itself but caused a functional blockade of muscarinic receptor-mediated inhibition of adenylate cyclase activity. The reversible binding characteristics of both BM 123 and BM 123A were investigated in competitive binding experiments with N-[3H]methylscopolamine at 0 degree C, conditions under which little or no receptor alkylation occurs. The concentration of BM 123A required for half-maximal receptor occupancy was similar to that of oxotremorine-M whereas the parent mustard (BM 123) was 200-fold less potent. GTP (10 microM) had no significant effect on the binding of N-methylscopolamine but caused a 16-fold increase in the concentration of BM 123A required for half-maximal receptor occupancy.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001388:Aziridines / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008433:Mathematics; D009206:Myocardium / Q000201:enzymology*; D019832:N-Methylscopolamine; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000494:pharmacology
chemical_list: D001388:Aziridines; D001389:Azirines; D011760:Pyrrolidinones; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C003025:N-(4-(2-chloroethylmethylamino)-2-butynyl)-2-pyrrolidone; D010095:Oxotremorine; C042743:oxotremorine M; D006160:Guanosine Triphosphate; D000262:Adenylyl Cyclases; D019832:N-Methylscopolamine