BIOCHEMICAL, NEUROPHYSIOLOGICAL, AND BEHAVIORAL-EFFECTS OF WY-45,233 AND OTHER IDENTIFIED METABOLITES OF THE ANTIDEPRESSANT VENLAFAXINE

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 beta-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, alpha-1-adrenergic, histamine-1, or opiate (mu) 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.