Amide, urea, and carbamate analogues of the muscarinic agent [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride.
A series of amide, urea, and carbamate analogues of the muscarinic (M1) ganglionic stimulant [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride (McN-A-343; 1) was prepared. The C1-methyl-substituted carbamates 8-11 were resolved into the enantiomers. In order to investigate the ganglionic stimulant activity and affinity of the new compounds we studied their ability to increase mean arterial blood pressure (MAP) in the pithed rat and their ability to displace the M1 receptor selective antagonist [3H]pirenzepine from rabbit sympathetic ganglia. The quaternary ammonium derivatives of 1, but not their corresponding tertiary amines, displayed ganglionic stimulant properties. The urea derivative 14 and the acetamide derivative 18 were almost equipotent to 1 as ganglionic agonists. In addition, 14 and 18 showed only 2- to 3-fold less affinity to ganglionic muscarinic receptors than 1. Introduction of a methyl group in the 1 position of the butynyl chain of 1 and its 4-chlorophenyl analogue increased ganglionic stimulant potency. The resulting (+/-)-9 and (+/-)-11 were the most potent analogues in this study. They were found to be partial agonists and showed 5- and 16-fold higher potency than 1, respectively, in increasing the MAP. They also displayed 6- and 18-fold higher affinity than 1 for ganglionic M1 receptors. The (S)-enantiomers of 9 and 11 were 1.5- and 4.9-fold more potent, respectively, than their antipodes as ganglionic muscarinic stimulants. The C1-methyl-substituted urea and acetamide derivatives (15 and 19) were 1.5- and 3-fold less potent than 1 and displayed several-fold lower affinity for ganglionic M1 receptors. The new quaternary analogues retained the selectivity for ganglionic muscarinic receptors since they produced weak partial agonist effects on the guinea pig ileum and showed several-fold lower nicotinic activity than 1 in the frog rectus abdominis assay.
Nilsson
B M
BM
Department of Organic Pharmaceutical Chemistry, University of Uppsala, Sweden.
Vargas
H M
HM
Hacksell
U
U
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003714:Denervation; D005724:Ganglia / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009132:Muscles / Q000187:drug effects; D010277:Parasympathomimetics / Q000737:chemistry / Q000494:pharmacology*; D010890:Pirenzepine / Q000378:metabolism; D011817:Rabbits; D011898:Ranidae; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride