Dual-acting agents for improving cognition and real-world function in Alzheimer's disease: Focus on 5-HT6 and D3 receptors as hubs

Millan, Mark J.; Dekeyne, Anne; Gobert, Alain; Brocco, Mauricette; Mannoury la Cour, Clotilde; Ortuno, Jean Claude; Watson, David; Fone, Kevin C.F.

Abstract

© 2020 Elsevier Ltd To date, there are no interventions that impede the inexorable progression of Alzheimer's disease (AD), and currently-available drugs cholinesterase (AChE) inhibitors and the N-Methyl-D-Aspartate receptor antagonist, memantine, offer only modest symptomatic benefit. Moreover, a range of mechanistically-diverse agents (glutamatergic, histaminergic, monoaminergic, cholinergic) have disappointed in clinical trials, alone and/or in association with AChE inhibitors. This includes serotonin (5-HT) receptor-6 antagonists, despite compelling preclinical observations in rodents and primates suggesting a positive influence on cognition. The emphasis has so far been on high selectivity. However, for a multi-factorial disorder like idiopathic AD, 5-HT6 antagonists possessing additional pharmacological actions might be more effective, by analogy to “multi-target” antipsychotics. Based on this notion, drug discovery programmes have coupled 5-HT6 blockade to 5-HT4 agonism and inhibition of AchE. Further, combined 5-HT6/dopamine D3 receptor (D3) antagonists are of especial interest since D3 blockade mirrors 5-HT6 antagonism in exerting broad-based pro-cognitive properties in animals. Moreover, 5-HT6 and dopamine D3 antagonists promote neurocognition and social cognition via both distinctive and convergent actions expressed mainly in frontal cortex, including suppression of mTOR over-activation and reinforcement of cholinergic and glutamatergic transmission. In addition, 5-HT6 blockade affords potential anti-anxiety, anti-depressive and anti-epileptic properties, and antagonising 5-HT6 receptors may be associated with neuroprotective (“disease-modifying”) properties. Finally D3 antagonism may counter psychotic episodes and D3 receptors themselves offer a promising hub for multi-target agents. The present article reviews the status of “R and D” into multi-target 5-HT6 and D3 ligands for improved treatment of AD and other neurodegenerative disorders of aging. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Citation

Millan, M. J., Dekeyne, A., Gobert, A., Brocco, M., Mannoury la Cour, C., Ortuno, J. C., …Fone, K. C. (2020). Dual-acting agents for improving cognition and real-world function in Alzheimer's disease: Focus on 5-HT6 and D3 receptors as hubs. Neuropharmacology, 177, Article 108099. https://doi.org/10.1016/j.neuropharm.2020.108099

• Journal Article Type: Review
• Acceptance Date: Apr 3, 2020
• Online Publication Date: Jun 7, 2020
• Publication Date: Oct 15, 2020
• Deposit Date: May 6, 2021
• Publicly Available Date: Jun 8, 2021
• Journal: Neuropharmacology
• Print ISSN: 0028-3908
• Electronic ISSN: 1873-7064
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 177
• Article Number: 108099
• DOI: https://doi.org/10.1016/j.neuropharm.2020.108099
• Public URL: https://nottingham-repository.worktribe.com/output/4831825
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0028390820301672?via%3Dihub