P4‐373: APN1125: A NOVEL A7 NICOTINIC ACETYLCHOLINE RECEPTOR PARTIAL AGONIST

Modulation of the α 7 nicotinic acetylcholine receptor (NAChR) has become a prime target for affecting cognition in several CNS diseases, including schizophrenia and Alzheimer's disease (AD). Compounds can modulate activity at this ligand-gated calcium channel in several ways including positive allosteric modulation (PAM), full agonism and/or partial agonism. Positive Phase 2 clinical results in AD using various measures of memory and cognition have further supported targeting the α 7 NAChR with partial agonists for therapy. APN1125 is a partial agonist active at the α 7 NAChR and demonstrates activity in pharmacologic models, with a profile compatible with development as a candidate drug. APN1125 was determined to bind to the acetylcholine (ACh) site of the α 7 NAChR through displacement of α -bungarotoxin binding to rat hippocampal membrane preparations (assay conducted by Perkin-Elmer). In vitro ADME and selectivity properties were determined in standard commercial assays. Agonist activity was measured using two-electrode voltage-clamp recordings in Xenopus laevis oocytes microinjected with mRNA expressing human α 7 NAChR. Cognition was tested in a natural forgetting Novel Object Recognition (NOR) task in male Wistar rats with a 1 h pre-treatment interval (Prime Behavior Testing Labs, Evans, GA, USA). APN1125 displaces α -bungarotoxin in the α 7 binding pocket with a K i of 48 nM. The compound was also shown to act as a partial agonist in an oocyte assay with an EC 50 of 1.16 μ M and an E max of 41% of the full acetylcholine response, with selectivity against hERG and 5HT3 receptors measured in functional assays. APN1125 is active in the natural forgetting NOR task over a broad dose range (1-30 mg/kg) using a one hour pre-test oral administration. APN1125 is an attractive development candidate for the treatment of cognitive dysfunction in schizophrenia, AD and potentially other CNS disorders. It was found to be a partial agonist with promising ADME and PK characteristics. APN1125 improves cognition in NOR over a broad dose range, with properties favorable for drug development.