Sensory gating deficits and deficiencies in executive function in neurological diseases, such as schizophrenia, have been linked to pathological deficits in ?-aminobutyric acidA (GABAA) and a7 nicotinic acetylcholine (nACh) receptors. We have previously described a series of selective type I positive allosteric modulators (PAMs) of a7 nACh receptors that are active in animal models of cognition. We have found that this effect can be potentiated in vivo with a positive modulator of GABAA receptors. Modifications to this series of compounds resulted in a series of PAMs that have dual activity at both GABAA and a7 nACh receptors. A structure activity relationship developed around these dual modulators led to varying ratios of modulation of a7 nACh and GABAA receptors. This directed polypharmacy is proposed to be advantageous in diseases of a polygenic origin, such as schizophrenia.

?-Aminobutyric acid<sub>A</sub> receptor positive allosteric modulators potentiate a7 nicotinic acetylcholine receptor mediated nootropic-effect

248th National Meeting (2014)

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?-Aminobutyric acidA receptor positive allosteric modulators potentiate a7 nicotinic acetylcholine receptor mediated nootropic-effect

?-Aminobutyric acid_A receptor positive allosteric modulators potentiate a7 nicotinic acetylcholine receptor mediated nootropic-effect