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Data are from Barlow, R. B.: Introduction to Chemical Pharmacology. London, Methuen and Co., 1964; Welsh, A. D., and Roepke, M. H.: J. Pharmacol. Exp. Ther. 55:118, 1935; Stehle, K. L., Melville, K. J., and Oldham, F. K.: J. Pharmacol. Exp. Ther. 56:473, 1936; Holton, P., and Ing, H. R.: Br. J. Pharmacol. 4:190, 1949; Ing, H. R., Kordik, P., and Tudor Williams, D. P. H.: Br. J. Pharmacol. 7:103, 1952. "Reduces effect of acetylcholine.

Data are from Barlow, R. B.: Introduction to Chemical Pharmacology. London, Methuen and Co., 1964; Welsh, A. D., and Roepke, M. H.: J. Pharmacol. Exp. Ther. 55:118, 1935; Stehle, K. L., Melville, K. J., and Oldham, F. K.: J. Pharmacol. Exp. Ther. 56:473, 1936; Holton, P., and Ing, H. R.: Br. J. Pharmacol. 4:190, 1949; Ing, H. R., Kordik, P., and Tudor Williams, D. P. H.: Br. J. Pharmacol. 7:103, 1952. "Reduces effect of acetylcholine.

the receptor site. A comparison of the cholinergic activity of a series of alkyltrimethylammonium compounds [R-N+(CH3), R = Ci-C9] shows n-amyltrimethylammonium,38 which may be considered to have a size and mass similar to those of ACh and to be one magnitude weaker as a muscarinic agonist. The presence of the acetyl group in ACh is not as critical as the size of the molecule. Studying a series of n-alkyltrimethylammonium salts revealed39 that for maximal muscarinic activity, the quaternary ammonium group should be followed by a chain of five atoms; this has been referred to as the five-atom rule.

Shortening or lengthening the chain of atoms that separates the ester group from the onium moiety reduces muscarinic activity. An a substitution on the choline moiety decreases both nicotinic and muscarinic activity, but mus-carinic activity is decreased to a greater extent. Nicotinic activity is decreased to a greater degree by substitution on the 3 carbon. Therefore, acetyl a-methylcholine, although less potent than ACh, has more nicotinic than muscarinic activity, whereas acetyl-3-methylcholine (methacholine) exhibits more muscarinic than nicotinic activity. Hydrolysis by AChE is more affected by substitutions on the 3 than the a carbon. The hydrolysis rate of racemic acetyl ยก-methy-lacetylcholine is about 50% of that of ACh; racemic acetyl a-ACh is hydrolyzed about 90% as fast.

Oxotremorine. Oxotremorine [1-(-pyrrolidono)-4-pyrrolidino-2-butyne] has been regarded as a CNS muscarinic stimulant. Its action on the brain produces tremors in experimental animals. It increases ACh brain levels in rats up to 40% and has been studied as a drug in the treatment of Alzheimer disease. Although earlier studies suggested that

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