RT Journal Article
SR Electronic
T1 An Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor Possessing Cognition-Enhancing Properties in Vivo
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 294
OP 307
DO 10.1124/jpet.107.120436
VO 323
IS 1
A1 Daniel B. Timmermann
A1 Jens Halvard Grønlien
A1 Kathy L. Kohlhaas
A1 Elsebet Ø. Nielsen
A1 Eva Dam
A1 Tino D. Jørgensen
A1 Philip K. Ahring
A1 Dan Peters
A1 Dorte Holst
A1 Jeppe K. Chrsitensen
A1 John Malysz
A1 Clark A. Briggs
A1 Murali Gopalakrishnan
A1 Gunnar M. Olsen
YR 2007
UL http://jpet.aspetjournals.org/content/323/1/294.abstract
AB Augmentation of nicotinic α7 receptor function is considered to be a potential therapeutic strategy aimed at ameliorating cognitive and mnemonic dysfunction in relation to debilitating pathological conditions, such as Alzheimer's disease and schizophrenia. In the present report, a novel positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR), 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea (NS1738), is described. NS1738 was unable to displace or affect radioligand binding to the agonist binding site of nicotinic receptors, and it was devoid of effect when applied alone in electrophysiological paradigms. However, when applied in the presence of acetylcholine (ACh), NS1738 produced a marked increase in the current flowing through α7 nAChRs, as determined in both oocyte electrophysiology and patch-clamp recordings from mammalian cells. NS1738 acted by increasing the peak amplitude of ACh-evoked currents at all concentrations; thus, it increased the maximal efficacy of ACh. Oocyte experiments indicated an increase in ACh potency as well. NS1738 had only marginal effects on the desensitization kinetics of α7 nAChRs, as determined from patch-clamp studies of both transfected cells and cultured hippocampal neurons. NS1738 was modestly brain-penetrant, and it was demonstrated to counteract a (–)-scopolamine-induced deficit in acquisition of a water-maze learning task in rats. Moreover, NS1738 improved performance in the rat social recognition test to the same extent as (–)-nicotine, demonstrating that NS1738 is capable of producing cognitive enhancement in vivo. These data support the notion that α7 nAChR allosteric modulation may constitute a novel pharmacological principle for the treatment of cognitive dysfunction. The American Society for Pharmacology and Experimental Therapeutics