Rl. Papke et al., The activation and inhibition of human nicotinic acetylcholine receptor byRJR-2403 indicate a selectivity for the alpha 4 beta 2 receptor subtype, J NEUROCHEM, 75(1), 2000, pp. 204-216
Human nicotinic acetylcholine (ACh) receptor subtypes expressed in Xenopus
oocytes were characterized in terms of their activation by the experimental
agonist RJR-2403. Responses to RJR-2403 were compared with those evoked by
ACh and nicotine. These agonists were also characterized in terms of wheth
er application of the drugs had the effect of producing a residual inhibiti
on that was manifest as a decrease in subsequent control responses to ACh m
easured 5 min after the washout of the drug. For the activation of alpha 4
beta 2 receptors, RJR-2403 had an efficacy equivalent to that of ACh and wa
s more potent than ACh. RJR-2403 was less efficacious than ACh for other hu
man receptor subtypes, suggesting that it is a partial agonist for all thes
e receptors. Nicotine activated peak currents in human alpha 4 beta 2 and a
lpha 3 beta 2 receptors that were 85 and 50% of the respective ACh maximum
responses. Nicotine was an efficacious activator of human alpha 7 receptors
, with a potency similar to ACh, whereas RJR-2403 had very low potency and
efficacy for these receptors. At concentrations of <1 mM, RJR-2403 did not
produce any residual inhibition of subsequent ACh responses for any recepto
r subtype. in contrast, nicotine produced profound residual inhibition of h
uman alpha 4 beta 2, alpha 3 beta 2, and alpha 7 receptors with IC50 values
of 150, 200, and 150 mu M, respectively. Go-expression of the human alpha
5 subunit with alpha 3 and beta 2 subunits had the effect of producing prot
racted responses to ACh and increasing residual inhibition by ACh and nicot
ine but not RJR-2403. in conclusion, our results, presented in the context
of the complex pharmacology of nicotine for both activating and inhibiting
neuronal nicotinic receptor subtypes, suggest that RJR-2403 will be a poten
t and relatively selective activator of human alpha 4 beta 2 receptors.