LL-00066471, a novel positive allosteric modulator of alpha 7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization

alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of alpha 7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. alpha 7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric alpha 7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of alpha 7 nAChR ion-channel. Here we describe a novel alpha 7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a alpha-bungar degrees toxin (alpha-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.