Eur J Pharmacol 2012 Jul 05;6861-3:41-9. doi: 10.1016/j.ejphar.2012.04.047.

Inhibitory effects of dextrorotatory morphinans on the human 5-HT(3A) receptor expressed in Xenopus oocytes: Involvement of the N-terminal domain of the 5-HT(3A) receptor.

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We previously developed a series of dextromethorphan (DM, 3-methoxy-17-methylmorphinan) analogs modified at positions 3 and 17 of the morphinan ring system. Recent reports have shown that DM attenuates abdominal pain caused by irritable bowel syndrome, and multidrug regimens that include DM prevent nausea/vomiting following cancer surgery. However, little is known regarding the molecular mechanisms underlying the beneficial effects of DM. Here, we investigated the effects of DM, 3 of its analogs (AM, 3-allyloxy-17-methoxymorphian; CM, 3-cyclopropyl-17-methoxymorphinan; and DF, 3-methyl-17-methylmorphinan), and 1 of its metabolites (HM, 3-methoxymorphinan) on the activity of the human 5-HT(3A) receptor channel expressed in Xenopus laevis oocytes, using the 2-microelectrode voltage clamp technique. We found that intra-oocyte injection of human 5-HT(3A) receptor cRNAs elicited an inward current (I(5-HT)) in the presence of 5-HT. Cotreatment with AM, CM, DF, DM, or HM inhibited I(5-HT) in a dose-dependent, voltage-independent, and reversible manner. The IC(50) values for AM, CM, DF, DM, and HM were 24.5±1.4, 21.5±4.2, 132.6±35.8, 181.3±23.5, and 191.3±31.5μM, respectively. The IC(50) values of AM and CM were 7-fold lower than that of DM, and mechanistic analysis revealed that DM, DF, HM, AM, and CM were competitive inhibitors of I(5-HT). Point mutations of Arg241 in the N-terminal, but not amino acids in the pore region, to other amino acid residues attenuated or abolished DM- and DM-analog-induced inhibition of I(5-HT). Together, these results demonstrated that dextrorotatory morphinans might regulate 5-HT(3A) receptor channel activity via interaction with its N-terminal domain.

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Species referenced: Xenopus laevis
Genes referenced: adm