Relationship Between Anti‐acetylcholine and Anti‐tremorine Activity in Anti‐parkinsonian and Related Drugs

Abstract

The anti-acetylcholine potency of a number of anti-Parkinsonism drugs and related phenQthiazine compounds was determined using the isolated guinea-pig ileum. The antagonism was assessed by the difference between the pA2 and pAio values and by log concentration-response curves for acetylcholine in presence and absence of the antagonists. All compounds except chlorpromazine showed some evidence of competitive antagonism to acetylcholine. The anti-tremor potency of the compounds was assessed from suppression of Tremorine-induced tremors in mice. There was a relation between anti-acetyIcholine and anti-Tremorine potency among the antiParkinsonism drugs, but not among the phenothiazine compounds. Some implications of the findings are discussed in relation to the mode of action of anti-Parkinsonism drugs.To explain the effectiveness of atropine in the treatment of Parkinsonism, Feldberg (1945) suggested the possibility of an atropine-acetyicholine antagonism at central synapses. Since then a number of synthetic drugs have been introduced for the treatment of Parkinsonism, all having peripheral and central atropine-like properties. Jenkner & Ward (1953) have suggested that, in experimental lesions producing Parkinsonian-like tremors, the disconnected neurones in the medial reticular formation become hypersensitive to endogenous acetylcholine released from near-by uninvolved cells. If human Parkinsonian tremor results from central hypersensitivity to acetylcholine, then it is reasonable to expect that effective antiParkinsonism drugs would be specific antagonists of acetylcholine.As no comprehensive quantitative assessment of the anti-acetylcholine potency of the anti-Parkinsonism drugs has yet been made, the present work was undertaken to measure anti-acetylcholine activity and its relation to anti-tremor potency in drug-induced tremor in mice. METHODSMeasurement of anti-acetylcholine potency. Estimations of pA2 and pAio values were carried out essentially according to the method of Schild (1947). Pieces of distal ileum were removed from freshly killed guinea-pigs which had been fasted overnight. The organ bath,

Some Pharmacological Studies on the Optically Active Isomers of Hyoscine and Hyoscyamine

“…A comparison of the effects of hyoscine and hyoscyamine in tests presumed to measure central activity showed hyoscine to be considerably more active. Ahmed & Marshall (1962) found (-)-hyoscine to be more effective than atropine against tremorine-induced tremor in mice, as did Vernier & Unna (1953) in monkeys. Janssen, Jageneau & Niemegeers (1960), using a similar fighting mice test to ours, found hyoscine to be forty-times as effective in blocking the fighting episodes.…”

A Comparison of the Effects of Chlorpromazine and Some Related Phenothiazines in Reducing the Rigidity of the Decerebrate Cat and in Some Other Central Actions

“…Promethazine had approximately I the potency of chlorpromazine in the decerebrate cat. In addition to its well-known anti-histaminic properties, promethazine has potent anti-cholinergic activity and is clinically useful in the treatment of Parkinsonian rigidity (Ahmed & Marshall, 1962;Duvoisin, 1965). We thus wondered to what extent the activity of promethazine was related to its anti-cholinergic property which is thought to be related to the anti-Parkinsonian action.…”

Modification of drug-induced catatonia and tremors by quipazine in rats and mice.

“…The failure of these agents to diffuse from the cerebrospinal fluid (20) or the fact that quipazine may be acting through one of its metabolites generated in the systemic circulation, most likely by the liver, may serve as an explanation for these effects. The effects of tremorine are considered to be due to its muscarinic activity and can be blocked by atropine and related agents (21). Quipazine is only one-ten thousandth as active as atropine on the isolated guinea pig ileum (1).…”