[Abstract Title]. - Society for Neuroscience

Disclosures: T. McCormack, None; E.A. Gay, None; J.L. Yakel , This research was supported
by the Intramural Research Program of the NIH, National Institute of Environmental Health
Sciences, A. Employment (full or part-time).
Poster
233. Nicotinic Aacetylcholine Receptors: Regulation and Function II
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 233.5/C7
Topic: B.02.a. Nicotinic acetylcholine receptors in brain: Physiology and function
Title: (+/-)TC-5619 produce a profound desensitization of alpha-7 nicotinic receptor activated
currents in vitro
Authors: *F. W. JOW 1 , M. BOWLBY 1 , T. LOCK 1 , R. PERI 1 , D. KOWAL 1 , A. NENCINI 2 , S.
HAYDAR 1 , C. GHIRON 2 , G. TERTSAPPEN 2 , J. DUNLOP 1 ;
1 Neurosci. Discovery Res., Wyeth Res., Monmouth Junction, NJ; 2 Siena Biotech, Siena, Italy
Abstract: Alpha-7 (α7) nicotinic acetylcholine receptor (nAChR) agonists are promising
therapeutic candidates for the treatment of cognitive dysfunction associated with a variety of
disorders including schizophrenia and Alzheimer‟s disease, and a number of selective agonists
have now been disclosed. TC-5619 has recently been identified as a potent and full agonist at the
α7 nAChR. In this study we have examined the effect of (+/-)TC-5619 on α7 nAChR agonistevoked
currents in GH4C1 cells stably expressing the receptor. α7 nAChR agonist activity of
(+/-)TC-5619 was confirmed in a FLIPR based assay measuring agonist activation of calcium
flux. In electrophysiological experiments, sequential application of increasing concentrations of
acetylcholine to GH4C1/α7 cells produced a concomitant concentration-dependent increase in
the magnitude of evoked currents (EC50, 30 µM). Interestingly, sequential application of (+/-
)TC-5619 to GH4C1/ α7 cells resulted in small currents in the presence of low drug
concentration and no subsequent response when higher concentrations of compound were
applied. Cells treated with low concentrations of (+/-)TC-5619 were also found to be
unresponsive to subsequent addition of acetylcholine suggestive of a profound receptor
desensitization to these low drug concentrations. Potent α7 nAChR agonist activity of (+/-)TC-
5619 could be demonstrated by treating individual cells with a single concentration of drug and
constructing a concentration-response curve from data derived from multiple cells (EC50, 0.11
µM; Emax, 0.76). Similarly, a number of closely related (+/-)TC-5619 were found to be potent
α7 receptor agonists but only when evaluation of each concentration of drug was restricted to a
single cell. In contrast, a series of unrelated α7 nAChR agonists, representing diverse
chemotypes, e.g., SEN12333, were found to produce a similar concentration-dependent increase
in evoked currents, when applied sequentially to the same cell, as was observed with