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Study on the effect of EMD386088, a 5-HT 6 receptor partial agonist, in enhancing the anti-immobility action of some antidepressants in rats

Study on the effect of EMD386088, a 5-HT 6 receptor partial agonist, in enhancing the anti-immobility action of some antidepressants in rats

Magdalena Jastrzębska-Więsek, Agata Siwek, Anna Partyka, Marcin Kołaczkowski, Maria Walczak, Magdalena Smolik, Gniewomir Latacz, Katarzyna Kieć-Kononowicz, Anna Wesołowska

Naunyn Schmiedebergs Arch Pharmacol. 2018 Jan;391(1):37-49.

PMID: 29079874

Abstract:

The effect of some antidepressants co-administered with EMD386088 in the modified forced swim test in rats was investigated. Additionally, the pharmacokinetics, metabolic stability, and the effect of EMD386088 on P450 cytochromes were determined. Intraperitoneal (i.p.) coadministration of EMD386088 (2.5 mg/kg) and imipramine (15 mg/kg), reboxetine (5 mg/kg), moclobemide (10 mg/kg), or bupropion (10 mg/kg) evoked significant antidepressant-like activity, whereas no effect was observed after joint administration of EMD386088 with s-citalopram (10 mg/kg). Pharmacokinetic in vivo investigation showed a rapid absorption of EMD386088 (2.5 and 5 mg/kg) with t 1/2 = 67 min (t max = 5 min). Large volume of distribution (V d/F = 102 L/kg) indicated its penetration into peripheral compartments. The most active coadministration of EMD386088 (2.5 mg/kg) with imipramine (15 mg/kg) resulted in slower absorption of the compound (C max = 60 min) and decrease in the volume of distribution (V d/F = 32.2 L/kg). EMD386088 penetrates the blood-brain barrier with a high brain/plasma ratio of about 19 (2.5 mg/kg) and 7.5 for coadministration with imipramine. The in silico and in vitro studies on EMD386088 metabolic stability showed the dehydrogenation of tetrahydropyridine moiety as its main metabolic pathway. EMD386088 did not influence on CYP3A4 activity, and it has been classified as a very weak CYP2D6 inhibitor (IC 50 = 2.25 μM). The results obtained from the forced swim test in rats indicate that an activation of 5HT6 receptor may facilitate antidepressant-like activity of some antidepressants. The pharmacokinetic results suggest that the interaction between EMD386088 and imipramine could not have been pharmacokinetic in nature.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1171123468	EMD386088		1171123-46-8	Price

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