Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer’s disease

Introduction: There are significant efforts invested into the discovery and development of novel treatments for Alzheimer’s disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development.

Areas covered: The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words ‘5-HT6?, ‘cognition’, ‘dementia’, ‘Alzheimer’s disease’, ‘Phase II’ and ‘Phase III’ in various databases and from conference abstracts.

Expert opinion: After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.