Biochemical, neurophysiological, and behavioral effects of Wy‐45,233 and other identified metabolites of the antidepressant venlafaxine

Abstract

Abstract Seven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The O‐desmethyl compound Wy‐45,233, which is the major metabolite in man, had the greatest preclinical activity. This metabolite exhibited an antidepressant profile (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal β‐adrenergic subsensitivity) comparable to the parent drug, venlafaxine. This compound also inhibited serotonergic and noradrenergic firing rates like the parent compound, but with less potency. The cyclohexyl ring‐hydroxylated metabolite Wy‐47,877 and the N‐desmethyl metabolite Wy‐45, 494 were also active in reserpine hypothermia, but Wy‐45,494 was a weaker inhibitor of serotonin uptake and both metabolites were weaker inhibitors of norepinephrine uptake than Wy‐45,233. None of the seven metabolites tested exhibited significated binding at dopamine‐2, muscarinic cholinergic, α‐1‐adrenergic, histamine‐1, or opiate (μ) receptors. These results suggest that Wy‐45,233, the O‐desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side‐effect profile of venlafaxine.