Identification of α7 Nicotinic Acetylcholine Receptor Agonists for their Assessment in Improving Cognition in Schizophrenia

Abstract

The α7 nicotinic acetylcholine receptor (nAChR) has been a target of interest to the neuroscience area for the treatment of cognitive deficits in schizophrenia for some time. The pentameric α7 nAChR is the most abundant nAChR in the brain and consist of five α7 subunits, each with an orthosteric low affinity binding site for the endogenous agonist, acetylcholine. This account describes the discovery efforts undertaken at Pharmacia and Pfizer to identify novel agonists of the α7 nAChR. It establishes the importance of a robust High Throughput Screen (HTS) to identify high quality chemical matter, and the critical nature of lead optimization strategies to deliver a series of compounds to enter the clinical setting. In addition to the medicinal chemistry efforts, the full screening strategy and path to the clinic are described for compounds emerging from the synergies of merging two independent programs into one. This target remains a challenge within the pharmaceutical industry, which is charged with delivering innovative medicines to patients with schizophrenia.