PT  - JOURNAL ARTICLE
AU  - Xiao, Yingxian
AU  - Smith, Richard D.
AU  - Caruso, Frank S.
AU  - Kellar, Kenneth J.
TI  - Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs
DP  - 2001 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 366--371
VI  - 299
IP  - 1
4099  - http://jpet.aspetjournals.org/content/299/1/366.short
4100  - http://jpet.aspetjournals.org/content/299/1/366.full
SO  - J Pharmacol Exp Ther2001 Oct 01; 299
AB  - The opioid agonist properties of (±)-methadone are ascribed almost entirely to the (−)-methadone enantiomer. To extend our knowledge of the pharmacological actions of methadone at ligand-gated ion channels, we investigated the effects of the two enantiomers of methadone and its metabolitesR-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium perchlorate (EDDP) andR-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride (EMDP), as well as structural analogs of methadone, including (−)-α-acetylmethadol hydrochloride (LAAM) and (+)-α-propoxyphene, on rat α3β4 neuronal nicotinic acetylcholine receptors (nAChRs) stably expressed in a human embryonic kidney 293 cell line, designated KXα3β4R2. (±)-Methadone inhibited nicotine-stimulated 86Rb+ efflux from the cells in a concentration-dependent manner with an IC50 value of 1.9 ± 0.2 μM, indicating that it is a potent nAChR antagonist. The (−)- and (+)-enantiomers of methadone have similar inhibitory potencies on nicotine-stimulated 86Rb+ efflux, with IC50 values of approximately 2 μM. EDDP, the major metabolite of methadone, is even more potent, with an IC50value of approximately 0.5 μM, making it one of the most potent nicotinic receptor blockers reported. In the presence of (±)-methadone, EDDP, or LAAM, the maximum nicotine-stimulated86Rb+ efflux was markedly decreased, but the EC50 value for nicotine stimulation was altered only slightly, if at all, indicating that these compounds block α3β4 nicotinic receptor function by a noncompetitive mechanism. Consistent with a noncompetitive mechanism, (±)-methadone, its metabolites, and structural analogs have very low affinity for nicotinic receptor agonist binding sites in membrane homogenates from KXα3β4R2 cells. We conclude that both enantiomers of methadone and its metabolites as well as LAAM and (+)-α-propoxyphene are potent noncompetitive antagonists of α3β4 nAChRs. The American Society for Pharmacology and Experimental Therapeutics