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

✍ Scribed by Dr. Eric A. Muth; John A. Moyer; J. Thomas Haskins; Terrance H. Andree; G. E. Morris Husbands

• Publisher: John Wiley and Sons
• Year: 1991
• Tongue: English
• Weight: 514 KB
• Volume: 23
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/ddr.430230210

✦ Synopsis

Seven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The 0-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 p-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, a-1 -adrenergic, histamine-1 , or opiate (k) receptors. These results suggest that Wy-45,233, the 0-desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side-effect profile of venlafaxine.