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Vol. 60, Issue 1, 71-79, July 2001
7 Nicotinic Acetylcholine Receptor
by a Quaternary Analog of Cocaine
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
Ki 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.