Mm. Francis et al., Specific activation pf the alpha 7 nicotinic acetylcholine receptor by a quaternary analog of cocaine, MOLEC PHARM, 60(1), 2001, pp. 71-79
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.