The conversion of 2-chloroalkylamine analogues of oxotremorine to aziridinium ions and their interactions with muscarinic receptors in the guinea pig ileum.
Two mustard analogues of oxotremorine, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123) and N-[4-(2-chloromethylpyrrolidino)-2-butynyl]-2-pyrrolidone (BM 130), were synthesized. BM 123 and BM 130 cyclize in neutral aqueous solution to aziridinium ions. These aziridinium ions are potent stimulants of the guinea pig ileum. This agonist activity is unaffected by hexamethonium but is inhibited by methylatropine and by pretreatment of solutions of BM 123 and BM 130 with thiosulfate. The parent 2-chloroalkylamines and the alcohols formed by hydrolysis of the aziridinium ions have very weak pharmacological effects. Incubation of the isolated guinea pig ileum for 30 min with BM 123 at 20 microM and 2 microM caused 94% and 48% receptor alkylation, respectively, as calculated from the shift in the agonist dose-response curve. Similar incubations with BM 130 at 20 microM and 5 microM alkylated 85% and 63% of the receptors. No recovery from this apparent blockade was observed over a 4-hr time period. These calculated receptor occupancies by BM 123 and BM 130 agreed with those estimated from reduction of [3H] (-)-3-quinuclidinyl benzilate binding to homogenates of the ileum following exposure to BM 123 and BM 130. Methylatropine (20 nM) protected against the irreversible actions of BM 123 and BM 130. In homogenates of the guinea pig ileum, BM 123 and BM 130 also caused a selective reduction in the binding capacity of [3H]N-methylscopolamine without significantly affecting the apparent affinity. This inhibitory effect persisted after extensive washing. BM 130 was a weak agonist at nicotinic receptors of the frog rectus abdominis muscle, whereas BM 123 was almost inactive. In conclusion, BM 123 and BM 130 are potent and specific muscarinic agonists that bind irreversibly to muscarinic receptors.
D000478:Alkylation; D000818:Animals; D001388:Aziridines / Q000138:chemical synthesis* / Q000494:pharmacology; D001389:Azirines / Q000138:chemical synthesis*; D001667:Binding, Competitive; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000032:analysis; D006168:Guinea Pigs; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D007202:Indicators and Reagents; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects; D010095:Oxotremorine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011894:Rana pipiens; D011976:Receptors, Muscarinic / Q000378:metabolism*
D001388:Aziridines; D001389:Azirines; D002712:Chlorides; D007202:Indicators and Reagents; D011760:Pyrrolidinones; D011976:Receptors, Muscarinic; C003025:N-(4-(2-chloroethylmethylamino)-2-butynyl)-2-pyrrolidone; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; C043039:N-(4-(2-chloromethylpyrrolidino)-2-butynyl)-2-pyrrolidone