Despite therapeutic advances made in the treatment of positive symptoms associated with schizophrenia, the treatment of negative symptoms, including cognitive dysfunction, has not been adequately addressed.  Preclinical literature indicates that alpha7 nicotinic acetylcholine (a7 nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia and Alzheimer's Disease.  Though several a7 nACh receptor agonists have entered clinical trials in schizophrenia, many have hit developmental roadblocks due to efficacy, safety, or off-target issues.  We report herein a series of potent a7 nACh receptor partial agonists, built upon a novel quinuclidine-based scaffold, with high selectivity against other nicotinic receptor subtypes and the 5-HT3a receptor.  Optimal members of the series alleviate cognitive impairment and auditory gating deficits in pre-clinical models of schizophrenia.

Efficacy of novel α7 nicotinic acetylcholine receptor partial agonists in models of schizophrenia

243rd National Meeting (2012)

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