N-OXIDES OF PHENOTHIAZINE ANTIPSYCHOTICS - EFFECTS ON INVIVO AND INVITRO ESTIMATES OF DOPAMINERGIC FUNCTION

  • 1 January 1983
    • journal article
    • research article
    • Vol. 225  (3) , 539-545
Abstract
Although N-oxidation is a major route for the metabolism of tertiary amine drugs in humans, the extent to which N-oxide (NO) metabolites of clinically used phenothiazine antipsychotics contribute to the neuropharmacology of the parent drug has been uncertain. After direct lateral ventricular injection of rats, both fluphenazine-NO and trifluoperazine-NO (piperazinyl-4-NO) had significant antidopaminergic activity as shown by their antagonism of amphetamine-induced locomotion and, to a lesser extent, of apomorphine-induced stereotypy. In vitro, fluphenazine-NO and trifluoperazine-NO inhibited both [3H]spiperone binding to rat striatal membranes and dopamine-stimulated adenylate cyclase activity in striatal homogenates. Chlorpromazine (CPZ)-NO (side-chain oxide) did not have significant antidopaminergic activity in either in vitro test, nor did it block amphetamine or apomorphine-induced behavior when centrally administered. These latter results were surprising because it was reported that CPZ-NO had significant antidopaminergic activity when administered by i.p. injection. Administration of CPZ-NO or CPZ i.p. resulted in increased concentrations in brain of the acidic metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. For CPZ-NO, this occurred concomitantly with the peripheral conversion of the NO back to the parent drug. Although CPZ-NO does not itself have antidopaminergic properties, it may be readily converted to CPZ or other active species that contribute to pharmacological responses. The NO of the phenothiazines may contribute to the neuropharmacological actions of antipsychotic drugs via several mechanisms, and correlating metabolic and neuropharmacological data are necessary.