MCN-5652 - A HIGHLY POTENT INHIBITOR OF SEROTONIN UPTAKE

Abstract

McN-5652 is one of a series of substituted pyrrolo-isoquinolines that, as a group, potently inhibit the uptake of one or more of the monamines, norepinephrine, serotonin and dopamine. McN-5652 is characterized in exceptionally high potency as an inhibitor of the uptake of serotonin by rat brain synaptosomes in vitro (Ki .apprx. 0.6 nM) and ex vivo (ED50 .apprx. 2 mg/kg p.p.). The high potency of McN-5652 as a serotonin uptake inhibitor in vivo in indicated further by the low doses required to potentiate 5-5-hydroxytryptophan-induced head twitches in mice (ED50 = 0.4 mg/kg 2 hr after p.o. dosing) and the serotonin syndrome in rats (ED50 = 1.5 mg/kg 2 hr after p.o. dosing). McN-5652 also potently inhibited the synaptosomal uptake of norepinephrine (Ki .apprx. 3 nM) and was a moderately potent inhibitor of the synaptosomal uptake or dopamine (Ki .apprx. 40 nM). McN-5652 inhibited tetrabenazine-induced ptosis in rats and mice but was much less effective in blocking the sedation caused by tetrabenazine. In rats, McN-5652 did not induced the stereotyped behavior often caused by dopamine agonists and inhibitors of dopamine uptake. Receptor binding experiments indicated that McN-5652 has a weak affinity for serotonin 5-HT4 and alpha-1 adrenergic receptors (apparent Ki .apprx. 200 nM) and a very low affinity for dopamine D1 and D2 receptors, serotonin 5-HT1, alpha-2 adrenergic, muscarinic and .gamma.-aminobutyric acid-A receptors. Experiments using the guinea pig ileum indicate that McN-5652 is a weak, noncompetitive antagonist of histamine.