No abstract

Muth, E.A., J.A. Moyer, J.T. Haskins, T.H. Andree, and G.E. M. Husbands:Biochemical, neurophysiological, and behavioral effects of Wy-45,233 and other identified metabolites of the antidepressant venlafaxine. Drug Dev. Res. 23:191-199, 1991. 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 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.

No abstract

Several novel substituted gamma-carbolines were synthesized and examined in a series of in vitro and in vivo pharmacological tests to determine potential antipsychotic activity. Most compounds were orally active in blocking the conditioned avoidance response (CAR) in rats but did not antagonize apomorphine-induced stereotyped behavior. Compound 17 (Wy-47,384), a gamma-carboline with a 3-(3-pyridinyl)propyl side chain, was selected for development as an atypical antipsychotic agent because of its potent and selective profile in preclinical psychopharmacological tests. It blocked CAR in rats with an AB50 of 14 mg/kg po, showed weak affinity for the D2 receptor site (Ki = 104 nM), and showed differential potency in antagonizing apomorphine-induced stereotyped behavior (ED50 = 11 mg/kg ip) and climbing behavior (ED50 = 4 mg/kg ip). Such activities are suggestive of antipsychotic efficacy combined with a low potential for extrapyramidal side effect (EPS) liability.