UCI-40083, a selective positive allosteric modulator (PAM) of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), was designed and characterized by the team at UC Irvine. Its synthesis for the clinical trials and pre-clinical experiments in this NCDDDG Project will be peformed by medicinal chemists at Newport Scientific Inc., supervised by our team. We will work with Newport Scientific Inc. to conduct the assays and stability studies necessary for its formulation for human use. We will also work with Newport Scientific Inc. to support the assays in plasma and urine forthe Phase 1 and Phase 2 clinical trials. Because Phase 2 trials will be conducted in persons with schizophrenia who are treated with neurolepfic drugs, many of whom smoke cigarettes, the UC Irvine team will perform preclinical animal model studies to determine the effect of UCI-40083 on cognitive function in rats chronically treated with nicofine (to simulate smoking behavior) and/or haloperidol (to simulate antipsychofic treatment).
Persistent neurocognitive deficits, psychosocial disability, and negative symptoms are evidence that current neuroleptic therapies, which primarily inhibit dopamine D2 receptors, are insufficient treatment for schizophrenia. Alpha7-nicotinic receptor acfivation is a potential additional target for drug therapy. UCI- 40083 is the first of a new class of drug that can improve alpha7-nicotinic receptor function