The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

Abstract

Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile. Areas covered: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD. Expert opinion: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.

Direct visualization of cAMP signaling in primary cilia reveals up-regulation of ciliary GPCR activity following Hedgehog activation

“…The neuronal 5-HT 6 receptor has attracted much interest due to its apparent positive effect on memory consolidation and cognitive function (6). However, a recent series of clinical trials to test the effectiveness of 5-HT 6 antagonists on Alzheimer's disease yielded disappointing results (52). A more complete appreciation of how and where this GPCR functions could be key to developing more effective drugs.…”

Serotonin in Animal Cognition and Behavior

“…It has been recently stressed out for 5-HT 4 R and 5-HT 6 R subtypes [137,185]. Several 5-HT 6 R antagonists have been tested in recent clinical trials in Alzheimer patients although the results were mitigated [186]. Nonetheless, this field of research is complicated because, as mentioned above for other behavioral responses, 5-HTRs can act in the opposite manner, often in a different manner, in memory processes [183,184,187].…”

Alzheimer’s Disease Neuroprotection: Associated Receptors

“…Among the neuroprotective receptors, we can highlight the vitamin D receptor, responsible for vitamin D actions. Vitamin D is increasingly recognized as a substance involved in neuronal survival, taking part in psychiatric and [44,45].…”

“…Besides, 5HTR6 agonists have also been shown to have pro-cognitive effects. Partial or inverse agonists may produce promising cognitive effects [44,45]. Moreover, 5HTR6 gene variants can be a genetic risk factor for late-onset AD and 5HTR6 polymorphisms are possibly involved with AD susceptibility, such as the C267T polymorphism [44].…”