Cholinergic properties of choline ethers.
Effects of nine choline ethers, (CH3)3 NCH2CH(R)-O-R', on the muscarinic and nicotinic receptors of longitudinal smooth muscle of guinea-pig ileum were studied to understand the role of electronic/steric factors at the ether-oxygen in stimulating the cholinergic receptors. Their ED50S to cause contraction of the ileum in presence of hexamethonium (37 X 10(-6) M) were 2 to 307 times higher than that of acetylcholine (ACh; 2.9 X 10(-7) M). The relative maximal effects of 5 ethers (1.20 to 1.34) were higher than that of ACh (1.0), while 4 exhibited lower maximal effects (less than 0.71). These ethers exhibited no significant inhibition of choline acetyltransferase and cholinesterase activities from the longitudinal muscle at their ED50S. Hexamethonium significantly increased the ED50S of 5 choline ethers. The ED50S of some of the ethers also were significantly increased by treating the muscle with physostigmine (38.5 X 10(-8) M) or physostigmine and hexamethonium. Atropine (greater than 1 X 10(-6) M) blocked the contractions induced by these ethers. The steric hinderance caused by the beta-methyl and/or O-alkyl groups and the electron density around the ether-oxygen are limiting the muscarinic, as well as nicotinic, potencies of these choline ethers. Choline ethers possessing the beta-methyl and O-n-propyl, iso-propyl or ter-butyl groups presumably release ACh at a site causing inhibitory potential through a secondary pathway.
D000818:Animals; D002794:Choline / Q000031:analogs & derivatives / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002802:Cholinesterases / Q000378:metabolism; D004987:Ethers / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology; D010830:Physostigmine / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects*
D004987:Ethers; D011950:Receptors, Cholinergic; D010830:Physostigmine; D002795:Choline O-Acetyltransferase; D002802:Cholinesterases; D002794:Choline