1. LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization.
- Author
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Verma MK, Goel RN, Bokare AM, Dandekar MP, Koul S, Desai S, Tota S, Singh N, Nigade PB, Patil VB, Modi D, Mehta M, Gundu J, Walunj SS, Karche NP, Sinha N, Kamboj RK, and Palle VP
- Subjects
- Animals, Brain metabolism, Brain physiopathology, Cell Line, Tumor, Cholinergic Agents pharmacokinetics, Cognitive Dysfunction metabolism, Cognitive Dysfunction physiopathology, Cognitive Dysfunction psychology, Disease Models, Animal, Dogs, Exploratory Behavior drug effects, Gait Disorders, Neurologic metabolism, Gait Disorders, Neurologic physiopathology, Gait Disorders, Neurologic psychology, Ischemic Stroke drug therapy, Ischemic Stroke metabolism, Ischemic Stroke physiopathology, Male, Mice, Inbred BALB C, Open Field Test drug effects, Oxidative Stress drug effects, Rats, Sprague-Dawley, Rats, Wistar, Reflex, Startle drug effects, Signal Transduction, Social Behavior, alpha7 Nicotinic Acetylcholine Receptor metabolism, Mice, Rats, Behavior, Animal drug effects, Brain drug effects, Cholinergic Agents pharmacology, Cognition drug effects, Cognitive Dysfunction prevention & control, Gait Disorders, Neurologic prevention & control, Sensory Gating drug effects, alpha7 Nicotinic Acetylcholine Receptor drug effects
- Abstract
α7 nicotinic acetylcholine receptor (α7 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 α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca
2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-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., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2021
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