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1.
Eur J Pharmacol ; 947: 175625, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-36997046

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which affects cognitive functions with negative impact on day to day activities and an ultimate loss of independent living. Current standard of care (SOC) for AD, viz. donepezil, rivastigmine, galantamine, memantine etc. either alone or in combination show modest efficacy without changing the course of the disease. On prolonged treatment, side effects are more common with an eventual loss of efficacy. Aducanumab, a monoclonal antibody is a disease modifying therapeutic agent targeting the toxic amyloid beta (Aß) proteins for its clearance. However, it is found to have only modest efficacy in AD patients and its approval by FDA is controversial. Alternate, effective and safe therapeutics are need of the hour, as AD cases are expected to be doubled by 2050. Recently, 5-HT4 receptors have been envisioned as target for alleviating AD associated cognitive impairment with potential disease modifying ability impacting disease progression. Usmarapride is a 5-HT4 receptor partial agonist, being developed for the possible treatment of AD with symptomatic and disease modifying potential. Usmarapride demonstrated promising effects in ameliorating cognitive deficits in diverse animal models of episodic, working, social, and emotional memories. Usmarapride produced elevation in cortical acetylcholine levels in rats. Furthermore, usmarapride increased levels of soluble amyloid precursor protein alpha, a potential mechanism to reverse toxic Aß peptide pathology. Usmarapride also potentiated the pharmacological effects of donepezil in animal models. To conclude, usmarapride may be a promising intervention for alleviating the cognitive dysfunction in AD patients with disease modifying potential.


Assuntos
Doença de Alzheimer , Ratos , Animais , Doença de Alzheimer/metabolismo , Donepezila/farmacologia , Donepezila/uso terapêutico , Serotonina , Peptídeos beta-Amiloides/metabolismo , Rivastigmina/uso terapêutico
2.
Psychopharmacology (Berl) ; 239(7): 2215-2232, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35298691

RESUMO

RATIONALE: Ropanicant (SUVN-911) (3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo (3.1.0) hexane hydrochloride) is a novel α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist being developed for the treatment of depressive disorders. OBJECTIVES: Pharmacological and neurochemical characterization of Ropanicant to support a potential molecule for the treatment of depressive disorders. METHODS: Ropanicant was assessed for antidepressant-like activity using the rat forced swimming test (FST) and differential reinforcement of low rate -72 s (DRL-72 s). Alleviation of anhedonia was assessed in chronic mild stress model using sucrose preference test. To understand the mechanism of action, serotonin levels, ionized calcium-binding adaptor molecule 1 (Iba1), and brain-derived neurotrophic factor (BDNF) were determined. The onset of antidepressant-like activity was determined using the reduction in submissive behavior assay. The effects on cognition and sexual functions were assessed using the object recognition task and sexual dysfunction assay respectively. Interaction of Ropanicant, TC-5214, and methyllycaconitine (MLA) with citalopram was investigated individually in mice FST. RESULTS: Ropanicant exhibited antidepressant like properties in the FST and DRL-72 s. A significant reduction in anhedonia was observed in the sucrose preference test. Oral administration of Ropanicant produced a significant increase in serotonin and BDNF levels, with a reduction in the Iba1 activity. The onset of antidepressant like effect with Ropanicant was within a week of treatment, and was devoid of cognitive dulling and sexual dysfunction. While Ropanicant potentiated the effect of citalopram in FST, such an effect was not observed with MLA or TC-5214. CONCLUSIONS: Preclinical studies with Ropanicant support the likelihood of its therapeutic utility in the treatment of depressive disorders.


Assuntos
Antidepressivos , Transtorno Depressivo , Antagonistas Nicotínicos , Anedonia , Animais , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo , Citalopram/farmacologia , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Antagonistas Nicotínicos/farmacologia , Ratos , Receptores Nicotínicos , Serotonina , Sacarose , Natação
3.
J Med Chem ; 64(15): 10641-10665, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34251799

RESUMO

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Doença de Alzheimer/metabolismo , Transtornos Cognitivos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Agonistas do Receptor 5-HT4 de Serotonina/síntese química , Agonistas do Receptor 5-HT4 de Serotonina/química , Relação Estrutura-Atividade
4.
J Med Chem ; 61(11): 4993-5008, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29763304

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.


Assuntos
Amidas/química , Oxidiazóis/química , Oxidiazóis/farmacologia , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/química , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Animais , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Relação Estrutura-Atividade
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