[Abstract Title]. - Society for Neuroscience

Abstract: α7 nAChRs are considered as attractive targets for treating cognitive deficits in
schizophrenia and AD. Positive allosteric modulators (PAMs) may offer an advantage over
agonists by potentiating the function of α7 nAChRs. In this study, we describe a novel type II α7
PAM, A-867744 that exhibits a unique pharmacological profile based on radioligand binding. In
X. oocytes expressing hα7 nAChRs, A-867744 potentiated ACh evoked currents with an EC50 of
~ 1.2 κM and ~ 6.8-fold increase in maximal current amplitude. In the presence of 5 κM A-
867744, ACh evoked concentration-responses in oocytes expressing hα7 nAChRs were
potentiated by increases in potency, maximum efficacy, and Hill slope. In contrast, at hα4β2 and
hα3β4 subtypes expressed in HEK-293 cell lines, A-867744 did not potentiate nicotine-evoked
Ca 2+ responses. Rather, moderate inhibition of α4β2 and α3β4 was noted (IC50 values of ~ 2 and
20 κM, respectively). At h5-HT3A receptors expressed in oocytes, no effect of A-867744 (≤ 30
κM) was observed. At native α7 nAChRs, examined by whole cell patch clamp in rat
hippocampus CA1 or dentate gyrus brain slices, A-867744 (10 κM) enhanced α7 currents evoked
by ACh or choline, increased recovery from inhibition/desensitization, and potentiated choline
evoked spontaneous GABAergic synaptic activity. A-867744, similar to other α7 PAMs
(NS1738, TQS, and PNU-120596) did not displace the binding of [ 3 H]MLA to α7* or [ 3 H]
cytisine to α4β2* at ≤ 10 κM in rat cortex homogenates. However, unlike NS1738, TQS, and
PNU-120596, A-867744 displaced the binding of the agonist radioligand, [ 3 H]A-585539, in rat
cortex with a Ki of ~ 0.8 κM. In an α7-5-HT3A chimera composed of the extracellular N-terminus
domain of the α7 nAChR, A-867744 neither potentiated α7 agonist evoked responses nor
displaced [ 3 H]A-585539 binding, suggesting a site of action outside of the α7 N-terminal
domain. In summary, this study identifies a novel and selective α7 nAChR PAM that exhibits
unique pharmacological interaction with the receptor and will be further useful in addressing
mechanisms involved in allosteric modulation of the α7 nAChR.
Disclosures: J. Malysz, Abbott, A. Employment (full or part-time); J.H. Gronlien, Abbott, A.
Employment (full or part-time); D.J. Anderson, Abbott, A. Employment (full or part-time); M.
Haakerud, Abbott, A. Employment (full or part-time); K. Thorin-Hagene, Abbott, A.
Employment (full or part-time); H. Ween, Abbott, A. Employment (full or part-time); C.A.
Briggs, Abbott, A. Employment (full or part-time); R. Faghih, Abbott, A. Employment (full or
part-time); W.H. Bunnelle, Abbott, A. Employment (full or part-time); M. Gopalakrishnan,
Abbott, 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#: 233.11/C13
Topic: B.02.a. Nicotinic acetylcholine receptors in brain: Physiology and function