Specific activation pf the alpha 7 nicotinic acetylcholine receptor by a quaternary analog of cocaine

Effects of cocaine and cocaine methiodide were evaluated on the homomeric a lpha7 neuronal nicotinic receptor (nAChR). Whereas cocaine itself is a gene ral nAChR noncompetitive antagonist, we report here the characterization of cocaine methiodide, a novel selective agonist for the alpha7 subtype of nA ChR. Data from I-125-alpha -bungarotoxin binding assays indicate that cocai ne methiodide binds to alpha7 nAChR with a K-i value of approximately 200 n M while electrophysiology studies indicate that the addition of a methyl gr oup at the amine moiety of cocaine changes the drug's activity profile from inhibitor to agonist. Cocaine methiodide activates alpha7 nAChR with an EC 50 value of approximately 50 muM and shows comparable efficacy to ACh in oo cyte experiments. While agonist effects are specific for the alpha7 neurona l nAChR and are not observed with heteromeric neuronal or skeletal muscle n AChR, antagonist effects are present for heteromeric nAChR combinations. St udies of PC12 cells transiently transfected with human alpha7 cDNA and expr essing a variety of functional nicotinic receptor subtypes confirm the spec ificity of cocaine methiodide agonist effects. Our results indicate that a quaternary structural derivative of cocaine can be used as a specific agoni st for the alpha7 subtype of neuronal nicotinic receptor.