CHOLINERGIC ACTIVITIES OF HALOGENO-ACETYLCHOLINES

¹ Department of Pharmacology, Vanderbilt University School of Medicine, Nashciule, Tennessee

The cholinergic activities of fluoro-, chioro-, dichioro-, bromoand iodoacetylcholines (XACh where X = halogens) were investigated on the longitudinal muscle of guinea-pig ileum (for muscarinic activities), the frog rectus abdominis muscle (for nicotinic activities) and the rat phrenic nerve-diaphragm preparation (for blockade of transmission). Their muscarinic potencies could be arranged in the following order: ACh > FACh = ClACh = BrACh = IACh > Cl₂ACh. The steric volume occupied by any one of the halogeno-acetyl groups is larger than that of the acetyl radical of ACh. Therefore, the steric factors of halogenation are more significant than the electronic factors in limiting the muscarinic potencies of halogeno-ACh's. Their nicotinic potencies could be arranged in the following order: IACh > ACh > BrACh > ClACh > FACh > ClACh. The partial negative charge on the carbonyl oxygen decreases from IACh to Cl₂ACh because of the negative inductive effects of halogens. Therefore, the electronic factors of halogenation are more significant than the steric factors in the interaction of halogeno-ACh's at the nicotinic receptors. In the rat phrenic nervediaphragm preparation, all monohalogeno-ACh's produced neuromuscular blockade. The blockade produced by FACh and ClACh (ClACh > FACh) appeared to be of depolarizing type since 1) it was reversible; 2) it resembled that of decamethonium and there was initial potentiation of the muscle twitch before the blockade was produced; and 3) it was intensified by physostigmine sulfate and partly antagonized by d-tubocurarine chloride. The nature of the blockade produced by BrACh and IACh is yet to be determined. There was no initial potentiation of the muscle twitch with IACh and BrACh. An irreversible blockade (IACh > BrACh) followed by the contracture of the muscle was produced by IACh and BrACh. The irreversible blockade by iodoand bromo-compounds could be explained partially by their inherent capacity to alkylate—SH (or OH or > NH) groups of membrane proteins.