Specific activation of the alpha 7 nicotinic acetylcholine receptor by a quaternary analog of cocaine.
Effects of cocaine and cocaine methiodide were evaluated on the homomeric alpha 7 neuronal nicotinic receptor (nAChR). Whereas cocaine itself is a general nAChR noncompetitive antagonist, we report here the characterization of cocaine methiodide, a novel selective agonist for the alpha 7 subtype of nAChR. Data from (125)I-alpha-bungarotoxin binding assays indicate that cocaine methiodide binds to alpha 7 nAChR with a K(i) value of approximately 200 nM while electrophysiology studies indicate that the addition of a methyl group at the amine moiety of cocaine changes the drug's activity profile from inhibitor to agonist. Cocaine methiodide activates alpha 7 nAChR with an EC(50) value of approximately 50 microM and shows comparable efficacy to ACh in oocyte experiments. While agonist effects are specific for the alpha 7 neuronal nAChR and are not observed with heteromeric neuronal or skeletal muscle nAChR, antagonist effects are present for heteromeric nAChR combinations. Studies of PC12 cells transiently transfected with human alpha 7 cDNA and expressing a variety of functional nicotinic receptor subtypes confirm the specificity of cocaine methiodide agonist effects. Our results indicate that a quaternary structural derivative of cocaine can be used as a specific agonist for the alpha 7 subtype of neuronal nicotinic receptor.
Francis
M M
MM
Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
Cheng
E Y
EY
Weiland
G A
GA
Oswald
R E
RE
D000818:Animals; D001667:Binding, Competitive; D002038:Bungarotoxins / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019281:Dimerization; D007457:Iodine Radioisotopes; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007457:Iodine Radioisotopes; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C076070:cocaine methiodide; D003042:Cocaine