Journal Article

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders

Grandhi, Venkata Ramalingayya, Mohammed, Abdul Rasheed, Shinde, Anil, Benade, Vijay, Jasti, Venkat, Goyal, Vinod Kumar, Jayarajan, Pradeep, Nirogi, Ramakrishna, Abraham, Renny, Cummings, Jeffrey

2023

Overview

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer’s disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer’s type.

• Publisher: MDPI AG,MDPI
• Subject: 5-HT6 receptor antagonist / Aggression / Agitation / Alzheimer Disease - metabolism / Alzheimer's disease / Animal cognition / Animal models / Animals / Antipsychotics / avisetron / Behavior / Brain diseases / Brain research / cerlapirdine / Clinical trials / Cloning / Cognitive ability / Cyclin-dependent kinases / Dementia / Dementia disorders / Drug therapy / G protein-coupled receptors / idalopirdine / intepirdine / Localization / Memory / Mental disorders / Nervous system / Neurodegenerative diseases / Neurological diseases / Parkinson's disease / Pathogenesis / Patients / Proteins / Psychosis / Psychotropic drugs / R&D / Receptors / Receptors, Serotonin - metabolism / Research & development / Review / Schizophrenia / Serotonin / Serotonin Antagonists - therapeutic use / Serotonin S6 receptors / Testing