Diseases of cognitive impairment with polygenic origin, such as Alzheimer's or schizophrenia, may not respond adequately to a drug therapy that is selective for a single pharmacological target. Johnstone et al. sought to determine whether simultaneous allosteric modulation of ligand-gated ion channels, α5 GABAA receptors (GABAARs), and α7 nicotinic acetylcholine receptors (nAChRs) could produce synergistic effects on cognition. Indeed, combination of two allosteric modulators targeting α5 GABAARs and α7 nAChRs generated the expected long-term potentiation (LTP) activity in hippocampal slices. Interestingly, the compound 3-(2,5-difluorophenyl)-6-(N-ethylindol-5-yl)-1,2,4-triazolo[4,3-b]pyridazine (522-054), designed to simultaneously inhibit α5 GABAARs and enhance α7 nAChRs, produced the same LTP effect as the combination of the two allosteric modulators. In vivo, 522-054 produces behavioral effects expected for allosteric modulation of α5 GABAARs and α7 nAChRs in enhancing performance and facilitating attentional states. This synergistic strategy of dual allosteric modulation of different receptors mediating improved learning and memory in a single molecule may be translated into therapeutic efficacy in the management of Alzheimer's disease or other diseases of cognitive impairment.
See article at J Pharmacol Exp Ther 2011, 336:908–915.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics