Effects of dextrorotatory morphinans on alpha3beta4 nicotinic acetylcholine receptors expressed in Xenopus oocytes.
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 alpha3beta4 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-allyloxy-17-methoxymorphian; and CM, 3-cyclopropyl-17-methoxymorphinan) and one of its metabolites (HM; 3-methoxymorphinan), on neuronal alpha3beta4 nicotinic acetylcholine receptor channel activity expressed in Xenopus laevis oocytes, using the two-microelectrode voltage clamp technique. We found that intraoocyte injection of neuronal alpha3 and beta4 nicotinic acetylcholine receptor subunit cRNAs elicited an inward current (IACh) in the presence of acetylcholine. Co-treatment with DM, DF, AM, CM or HM inhibited IACh 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 microM, respectively. The order of potency for the inhibition of IACh was CM>HM>DF=AM>DM in oocytes expressing alpha3beta4 nicotinic acetylcholine receptors. The inhibitions of (IACh) 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 alpha3beta4 nicotinic acetylcholine receptor channel activity.
Department of Physiology, College of Veterinary Medicine, Konkuk University, Institute of Biomedical Science and Technology, and Bio/Molecular Informatics Center, Seoul, Republic of Korea.
Jun-Ho
JH
Lee
Eun-Joo
EJ
Shin
Sang Min
SM
Jeong
Jong-Hoon
JH
Kim
Byung-Hwan
BH
Lee
In-Soo
IS
Yoon
Joon-Hee
JH
Lee
Sun-Hye
SH
Choi
Sang-Mok
SM
Lee
Phil Ho
PH
Lee
Hyoung-Chun
HC
Kim
Seung-Yeol
SY
Nah
D000818:Animals; D002417:Cattle; D003915:Dextromethorphan / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D015870:Gene Expression; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014982:Xenopus laevis
D018075:RNA, Complementary; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D003915:Dextromethorphan