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Dexclamol: Effects on catecholamine metabolism and demonstration of stereochemical specificity of antagonism of central adrenergic receptors

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Summary

The effects of the benzocycloheptapyridoisoquinolinol derivative (+)-dexclamol · HCl and some of those of (±)-dexclamol and the corresponding (−)-dexclamol were compared to those of the potent neuroleptic agents droperidol and fluphenazine on norepinephrine (NE) and dopamine (DA) turnover in the whole brain and in the striatum of rats. Differences in NE and DA depletion following tyrosine hydroxylase inhibition with α-methyl-p-tyrosine indicated that (+)-dexclamol and droperidol increased DA turnover with no effect on NE turnover. At a higher dose both (+)-dexclamol and droperidol, but not (−)-dexclamol, accelerated DA turnover and also that of NE. A decrease in DA concentration occurred after both drugs under the latter condition only.

(+)-Dexclamol, (±)-dexclamol and droperidol exhibited a similar onset of action employing striatal homovanillic acid (HVA) increase as indicative of DA turnover changes. The duration of action of droperidol was shorter than for (+)-dexclamol and (±)-dexclamol; fluphenazine displayed a slower onset and longer duration of activity. The (−)-dexclamol was ineffective. (+)-Dexclamol, droperidol and phentolamine reduced the concentrations of 3H-NE in heart when given after the 3H-NE, a probable indication of increased NE release due to adrenergic receptor blockade.

The present findings demonstrate that the neuroleptic agent (+)-dexclamol, but not (−)-dexclamol, affects central DA and NE turnover and indicates a stereochemical specificity with respect to antagonism of central DA and NE receptors.

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  1. Biochemical Pharmacology Department, Ayerst Research Laboratories, H3C 3JI, Montreal, Quebec, Canada

    T. A. Pugsley & W. Lippmann

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  1. T. A. Pugsley
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Pugsley, T.A., Lippmann, W. Dexclamol: Effects on catecholamine metabolism and demonstration of stereochemical specificity of antagonism of central adrenergic receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 295, 117–122 (1976). https://doi.org/10.1007/BF00499442

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