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

NEUROPHARMACOLOGY

卷:177

Review

Millan, Mark J.¹  Dekeyne, Anne¹  Gobert, Alain¹  Brocco, Mauricette¹  la Cour, Clotilde Mannoury¹  Ortuno, Jean-Claude²  Watson, David³  Fone, Kevin C. F.³ 

[1] Inst Rech Servier, Ctr Therapeut Innovat Neuropsychiat, F-78290 Croissy Sur Seine, France

[2] Inst Rech Servier, Ctr Excellence Chem, F-78290 Croissy Sur Seine, France

[3] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham NG7 2UH, England

关键词: Social cognition;    Novel object recognition;    Prefrontal cortex;    Hippocampus;    mTOR;    Cognition;    Learning;    Memory;    Multi-target;    GABA;    Psychosis;    Amyloid;    Tau;    Dementia;   

DOI  :  10.1016/j.neuropharm.2020.108099

来源: Elsevier

【 摘 要 】

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'.

【 授权许可】

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