ABSTRACT
Some 3- and 4-bromophenyl and dimethylsulfonium analogues of the muscarinic agent [4-[[N-(3-chlorophenyl)-carbamoyl]oxy]-2-butynyl] trimethylammonium chloride (McN-A-343) (1) were synthesized. The new compounds were assayed for effects on arterial blood pressure in the pithed rat (ganglionic muscarinic activity). The dimethylsulfonium salts (13a-d) appeared to be partial agonists in relation to 1. The 4-bromophenyl-substituted trimethylammonium iodide 10d exceeded 1 in potency by 3-fold. The compounds retained the selectivity for ganglionic muscarinic receptors shown by 1 since they had only weak effects on the guinea pig ileum in vitro.
Subject(s)
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/pharmacology , Quaternary Ammonium Compounds/pharmacology , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/chemical synthesis , Animals , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Dose-Response Relationship, Drug , Ganglia, Parasympathetic/drug effects , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Methylation , Muscles/drug effects , Ranidae , Rats , Sulfuric AcidsABSTRACT
Preparation of analogs of 4-[N-(3-chlorophenyl) carbamoyloxy]-2-butynyltrimethylammonium chloride [1 (McN-A-343)], cis- and trans-4-[N-(4-chlorophenyl)carbamoyloxy]-2-butenyltrimethylammonium iodides (5 and 6), and the corresponding epoxides and cyclopropanes is reported. Pharmacological testing for ganglion-stimulating activity demonstrated that the trans olefin 6 and trans epoxide 8 have properties similar to 1, while the trans cyclopropane analog 10 was inactive. All cis compounds were inactive. The muscarinic ganglion-stimulating properties of the active compounds are interpreted in terms of similar fit at the receptor level by the alkyltrimethylammonium ion and the ether oxygen 5.7 A distant, as well as an electron-rich center midway between groups in the form of a double bond or unshared electron pairs. Comparison of smooth muscle and ganglion-stimulating properties of the compounds showed that trans epoxide 8 was the most selective for muscarinic ganglionic sites.
Subject(s)
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/chemical synthesis , Ganglionic Stimulants/chemical synthesis , Parasympathomimetics/chemical synthesis , Quaternary Ammonium Compounds/chemical synthesis , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/analogs & derivatives , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride/pharmacology , Alkenes/chemical synthesis , Alkenes/pharmacology , Animals , Blood Pressure/drug effects , Cats , Cyclopropanes/chemical synthesis , Cyclopropanes/pharmacology , Epoxy Compounds/chemical synthesis , Epoxy Compounds/pharmacology , Ileum/drug effects , In Vitro Techniques , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Rabbits , Receptors, Cholinergic/drug effectsABSTRACT
Preparation of analogs of 4-[N-(3-chlorophenyl)carbamoyloxy]-2-butynyltrimethylammonium chloride (1, McN-A-343), the isomeric 2-trimethylammoniomethyl-3-[N-(4-chlorophenyl)carbamoyloxymethyl]bicyclo [2.2.1]hept-5-ene iodides (10-13), and the corresponding -bicyclo[2.2.1]heptane iodides (14-17) are reported. None of the compounds demonstrated ganglion-stimulating activity similar to 1 or antagonized the effects of 1.
