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 P.; Brocco, Mauricette; Cour, Clotilde Mannoury la; Ortuno, Jean Claude; Watson, David J.; Fone, K.C.F.

doi:10.1016/j.neuropharm.2020.108099

Cited by 28 publications

(24 citation statements)

References 216 publications

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“…As a rule of thumb, increasing D3R function (e.g., agonism, increased receptor expression) generally impairs, while reducing D3R function (e.g., antagonism, lack of the receptor) improves cognitive and mnemonic performance [ 179 , 180 ]. The role of the D3R in cognition has been extensively reviewed earlier [ 102 , 168 , 181 ].…”

Section: Behavioral Functions Of the D3rsmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

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Section: Behavioral Functions Of the D3rsmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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“…Therefore, there is still urgent need of ongoing search for new compounds and treatments which will demonstrate grater efficacy in cognitive dysfunction connected with AD and related neurodegenerative diseases of aging. Moreover, the last literature dates indicate that it is important not to forego efforts to improve also the symptoms in patients at various stages of AD: from Mild Cognitive Impairment (MCI) to late-stage AD via mechanisms that not necessarily are directly involved into the pathological foundations of this disease [ 15 ]. Hence in our studies we assess also potential antidepressant- and anxiolytic-like activity of new compounds with procognitive potential.…”

Section: Introductionmentioning

confidence: 99%

The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

Sudoł

Cios

Jastrzębska-Więsek

et al. 2021

IJMS

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Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor.. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.

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“…receptor antagonism of YL-0919, a pharmacological property that has been pre-clinically shown to have antidepressant-like properties (Zajdel et al, 2016;Millan et al, 2020). Furthermore, the dosage range of YL-0919 in this animal model was similar to that in a rat model of chronic unpredictable stress Sun et al, 2019), which might indicate that YL-0919 could have a faster-onset antidepressant effect in the monkey model of depression.…”

Section: Discussionmentioning

confidence: 55%

The Faster-Onset Antidepressant Effects of Hypidone Hydrochloride (YL-0919) in Monkeys Subjected to Chronic Unpredictable Stress

Yin¹,

Tian²,

Fang

et al. 2020

Front. Pharmacol.

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Given the limited monkey models of depression available to date, as well as the procedural complexity and time investments that they involve, the ability to test the efficacy and time course of antidepressants in monkey models is greatly restricted. The present study attempted to build a simple and feasible monkey model of depression with chronic unpredictable stress (CUS) and evaluate the antidepressant effect and onset time of fluoxetine hydrochloride (FLX) and the new drug hypidone hydrochloride (YL-0919), a potent and selective 5-HT reuptake inhibitor, 5-HT1A receptor partial agonist and 5-HT6 receptor full agonist. Female cynomolgus monkeys with low social status in their colonies were selected and subjected to CUS for 8 weeks by means of food and water deprivation, space restriction, loud noise, strobe light, and intimidation with fake snakes. Huddling, self-clasping, locomotion and environmental exploration were monitored to evaluate behavioral changes. In addition, the window-opening test was used to evaluate the exploratory interest of the monkeys. The present results revealed that CUS-exposed monkeys displayed significant depression-like behaviors, including significant decreases in exploratory interest, locomotion, and exploration as well as significant increases in huddling and self-clasping behavior and the level of fecal cortisol after 8 weeks of CUS. Treatment with FLX (2.4 mg/kg, i. g.) or YL-0919 (1.2 mg/kg, i. g.) markedly reversed the depression-like behaviors caused by CUS, producing significant antidepressant effects. YL-0919 (once daily for 9 days) had a faster-onset antidepressant effect, compared with FLX (once daily for 17 days). In summary, the present study first established a CUS model using female cynomolgus monkeys with low social status and then successfully evaluated the onset time of 5-HTergic antidepressants. The results suggested that monkeys exposed to CUS displayed significant depression-like behaviors, and both FLX and YL-0919 produced antidepressant effects in this model. Moreover, YL-0919 appeared to act faster than FLX. The present study provides a promising prospect for the evaluation of fast-onset antidepressant drugs based on a CUS monkey model.

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

Cited by 28 publications

References 216 publications

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

The Faster-Onset Antidepressant Effects of Hypidone Hydrochloride (YL-0919) in Monkeys Subjected to Chronic Unpredictable Stress

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