RT Journal Article
SR Electronic
T1 Selective Inhibition of Acetylcholine-Evoked Responses of α7 Neuronal Nicotinic Acetylcholine Receptors by Novel tris- and tetrakis-Azaaromatic Quaternary Ammonium Antagonists
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 652
OP 666
DO 10.1124/mol.109.056176
VO 76
IS 3
A1 Gretchen Y. López-Hernández
A1 Jeffrey S. Thinschmidt
A1 Guangrong Zheng
A1 Zhenfa Zhang
A1 Peter A. Crooks
A1 Linda P. Dwoskin
A1 Roger L. Papke
YR 2009
UL http://molpharm.aspetjournals.org/content/76/3/652.abstract
AB A family of 20 tris-azaaromatic quaternary ammonium (AQA) compounds were tested for their inhibition of α7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes. The potency of inhibitory activity was related to the hydrophobic character of the tris head groups. Two tris-AQA compounds were studied in detail: the highly effective inhibitor 1,3,5-tri-[5-(1-quinolinum)-pent-1-yn-1-yl]-benzene tribromide (tPyQB) and the less potent antagonist 1,3,5,-tri-{5-[1-(2-picolinium)]-pent-1-yn-1-yl}benzene tribromide (tPy2PiB). In addition, we evaluated 1,2,4,5-tetra-{5-[1-(3-benzyl)pyridinium]pent-1-yl}benzene tetrabromide (tkP3BzPB), a tetrakis-AQA with very hydrophobic headgroups. We compared the activity of the AQA compounds to the frequently used α7-antagonist methyllycaconitine (MLA). Both tPyQB and tkP3BzPB were selective antagonists of α7. However, although inhibition by tPyQB was reversible within 5 min, the recovery time constant for tkP3BzPB inhibition was 26.6 ± 0.8 min, so that the equilibrium inhibition in the prolonged presence of nanomolar concentrations of tkP3BzPB was nearly 100%. The potency, selectivity, and slow reversibility of tkP3BzPB were comparable with or greater than that of MLA. The inhibitory actions of tPyQB, tPy2PiB, and tkP3BzPB were evaluated on the acetylcholine (ACh)-evoked responses of native nAChRs in rat brain slices. The α7-mediated responses of hippocampal interneurons were effectively reduced by 1 μM tPyQB and tkP3BzPB but not tPy2PiB. In rat medial septum, tkP3BzPB produced a greater inhibition of ACh-evoked responses of cells with fast inward currents (type I) than of cells with predominantly slow kinetics (type II), suggesting that tkP3BzPB can block α7 yet preserve the responsiveness of non-α7 receptors. These agents might be helpful in elucidating complex receptor responses in brain regions with mixed populations of nAChRs.