Drug interactions with dopamin-stimulated adenylate cyclasses of caudate nucleus and retina: direct agonist effect of a piribedil metabolite.

Dopamine- and apomorphine-stimulated adenylate cyclase activity, which is antagonized by neuroleptic drugs (pimozide, fulphenazine, chlorpromazine, haloperidol), is present in caudate nucleus and retina of several mammalian species. The presence of abeta-OH group in a catecholamine agonist decreases maximal efficacy without altering sensitivity in the cebus monkey caudate system, whereas only sensitivity is decreased in the bovine retinal system (Brown and Makman, 1972). The presence of N-methyl or N-isopropyl or even the more extensive side chain modification and N-substitution present in S 584 has little or no effect on sensitivity or maximal response in monkey caudate. Such features result in major species differences in response to agents such as IPNE. The potent direct stimulatory effect of S 584 but not of piribedil on adenylate cyclase, the indirect stimulation of cyclase by preincubation of intact caudate with piribedil, and the effect of piribedil on cAMP content of intact caudate suggest the following mode of action of piribedil: conversion in the caudate to a catechol metabolite (S 584), which in turn stimulates the postsynaptic adenylate cyclase system.