title: Serotonin 5-HT6Receptor 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-HT6receptor has received increasing attention, and a growing number of studies supported 5-HT6receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6receptors 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-HT6receptor 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-HT6receptor antagonists. Subsequently, the number of patents protecting 5-HT6chemical 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-HT6receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT6receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, C/Irunlarrea, 31008, Pamplona, Spain.
authors.forename: Hilda
authors.initials: H
authors.lastname: Ferrero
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, C/Irunlarrea, 31008, Pamplona, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Solas
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, C/Irunlarrea, 31008, Pamplona, Spain. mariaja@unav.es.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramirez
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor