Vol. 60, Issue 1, 71-79, July 2001

Specific Activation of the 7 Nicotinic Acetylcholine Receptor by a Quaternary Analog of Cocaine

Michael M. Francis, Elaine Y. Cheng, Gregory A. Weiland, and Robert E. Oswald

Department of Molecular Medicine, Cornell University, Ithaca, New York

Effects of cocaine and cocaine methiodide were evaluated on the homomeric 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 7 subtype of nAChR. Data from ¹²⁵I--bungarotoxin binding assays indicate that cocaine methiodide binds to 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 7 nAChR with an EC₅₀ value of approximately 50 µM and shows comparable efficacy to ACh in oocyte experiments. While agonist effects are specific for the 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 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 7 subtype of neuronal nicotinic receptor.