Abstract

Effects of cocaine and cocaine methiodide were evaluated on the homomeric α7 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 α7 subtype of nAChR. Data from¹²⁵I-α-bungarotoxin binding assays indicate that cocaine methiodide binds to α7 nAChR with aK _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 α7 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 α7 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 α7 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 α7 subtype of neuronal nicotinic receptor.