Role of alpha-2 adrenergic affinity in the action of a non-sedative antispasticity agent

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Abstract
Muscle hypertonus of central origin can be effectively reversed by either dopamine agonists or .alpha. adrenergic antagonists. Because of its efficacy in reversing reserpine rigidity (a syndrome resembling Parkinsonism), SKF-7265 [10-(2-dimethylaminoethyl)acridan] was examined to determine whether its action was mediated through .alpha.-adrenergic or dopaminergic receptors. The pharmacologic blocking activity of SKF-7265 was assessed by measuring blockade of the cardiovascular agonist responses induced by norepinephrine, epinephrine, isoproterenol, acetylcholine and histamine. The binding affinity of SKF-7265 was determined by displacement of 3H-spiperone from rat corpus striatum tissue and 3H-clonidine and 3H-WB-4101 [2-[N-(2,6-dimethoxyphenoxyethyl)]-aminomethyl-1,4-benzodioxane] displacement from rat cerebral cortical tissue. Using the cardiovascular responses, SKF-7265 was devoid of .beta.-adrenergic or cholinergic blocking effects and did not produce any behavioral or reflex deficits in awake animals. Receptor binding studies showed that SKF-7265 had equal affinity for .alpha.-1 and .alpha.-2 adrenergic receptors and little affinity for dopamine receptors. The efficacy which has been reported for the SKF-7265 induced reversal of reserpine rigdity and its potential value as an anti-spasticity agent may be attributed to its relatively high affinity for .alpha.-2 adrenergic receptors.