A series of novel pyridine compounds were synthesized and found to be type I positive allosteric modulators (PAMs) of a7 nicotinic receptors (nAChRs) by electrophysiology in Xenopus oocytes expressing human receptors.  Type I allosteric modulators do not retard the native kinetics of desensitization of the receptor leaving native signaling intact.  In addition some of these compounds were also found to be PAMs of ?-aminobutyric acidA (GABAA) receptors.  Additional modifications were made to achieve selectivity for GABAA �2/3 over �1 subtype containing receptors to reduce sedative activity as seen with a previous enaminone series.  a7 nAChRs have been identified as an important target for nootropics to improve cognitive defects in general.  In schizophrenia, both GABAA receptors and a7 nAChRs are important in regulating sensory gating.  Modulation of both targets with one drug can more effectively treat the negative symptoms and cognitive deficits associated with a polygenic disease such as schizophrenia.

Nootropics for use in schizophrenia: Dual positive allosteric modulation of α7 nAChR & GABA<sub>A</sub>R

243rd National Meeting (2012)

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Nootropics for use in schizophrenia: Dual positive allosteric modulation of α7 nAChR & GABAAR

Nootropics for use in schizophrenia: Dual positive allosteric modulation of α7 nAChR & GABA_AR