Serotonin 5-HT6 Receptor Antagonists in Alzheimer’s Disease: Therapeutic Rationale and Current Development Status

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT receptor has received increasing attention, and a growing number of studies supported 5-HT receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT receptor antagonists. Subsequently, the number of patents protecting 5-HT chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

“…This derivative at doses of 1 and 3 mg/kg enhanced short-term memory and improved cognitive flexibility in rats [80]. Although Phase II trials have not yet been concluded [81,82], this drug candidate could be useful in treating dementia in AD [83]. Another selective antagonist, AVN-322, which is a derivative of AVN-101 and AVN-211, is undergoing Phase I trials for AD and schizophrenia.…”

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

“…The procognitive properties of antagonists of the 5-HT 6 receptor have since been well-documented in preclinical animal models (Mitchell and Neumaier, 2005; Fone, 2008; Arnt et al, 2010; Meneses et al, 2011) that have also suggested a potential benefit of combining a 5-HT 6 receptor antagonist with an AChEI, as 5-HT 6 receptor antagonism was shown to potentiate the neurochemical, electrophysiological, and procognitive effects of the AChEI donepezil (Marcos et al, 2008; Dawson, 2011; de Bruin et al, 2011). Several 5-HT 6 receptor antagonists have now entered clinical development for the treatment of AD (Maher-Edwards et al, 2011; Wilkinson and Windfeld, 2014; Calhoun et al, 2017; Ferrero et al, 2017). Of these, idalopirdine (Lu AE58054), a high affinity ( Ki = 0.83 nm) and selective 5-HT 6 receptor antagonist (Arnt et al, 2010), is furthest advanced, and in phase III development for the treatment of mild to moderate AD as an adjunct therapy to AChEIs.…”

Age-Related Change in 5-HT6 Receptor Availability in Healthy Male Volunteers Measured with 11C-GSK215083 PET

“…Given that some of the potential indications, such as cognitive impairment in Alzheimer disease and age-related cognitive decline, are related to advancing age, it is important to understand the effects of age on 5-HT 6 receptors and to ascertain whether they remain an important target in older age groups. This importance is further underscored by recent negative results from 2 phase III trials of the 5-HT 6 antagonist idalopirdine for cognitive impairment in Alzheimer disease, despite promising results in preclinical studies (16).…”