Effects of dextrorotatory morphinans on α3β4 nicotinic acetylcholine receptors expressed in Xenopus oocytes

초록

We previously demonstrated that dextromethorphan (DM; 3-methoxy-17-methylmorphinan) analogs have neuroprotective effects, and a recent report showed that DM reduces the adverse effects of morphine and blocks alpha(3)beta(4) nicotinic acetylcholine receptors, a major target of anti-addictive agents. Here, we investigated the effects of DM, three of its analogs (DF, 3-methyl-17-methylmorphinan; AM, 3-altyloxy-17-methoxymorphian; and CM, 3-cyclopropyl-17-methoxymorphinan) and one of its metabolites (HM; 3-methoxymorphinan), on neuronal alpha(3)beta(4) nicotinic acetylcholine receptor channel activity expressed in Xenopus laevis oocytes, using the two-microelectrode voltage clamp technique. We found that intraoocyte injection of neuronal alpha 3 and beta 4 nicotinic acetylcholine receptor subunit cRNAs elicited an inward current (I-ACh) in the presence of acetylcholine. Co-treatment with DM, DF, AM, CM or HM inhibited IACI, in a dose-dependent, voltage-independent and reversible manner. The IC50 values for DM, DF, AM, CM and HM were 19.5 +/- 5.2, 15.8 +/- 4.5, 16.3 +/- 1.7, 10.1 +/- 2.8, and 13.5 +/- 4.0 mu M, respectively. The order of potency for the inhibition of I-ACh was CM > HM > DF = AM > DM in oocytes expressing alpha 3 beta 4 nicotinic acetylcholine receptors. The inhibitions of (I-ACh) by DM, DF and HM, AM and CM were non-competitive. These results indicate that AM, CM and HM could be novel non-competitive agents regulating alpha(3)beta(4) nicotinic acetylcholine receptor channel activity. (c) 2006 Elsevier B V. All rights reserved.

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