Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5)

Ni, Wei; Wang, Huan; Li, Xiaokang; Zheng, Xinyu; Wang, Manjiong; Zhang, Jian; Gong, Qi; Ling, Dazheng; Mao, Fei; Zhang, Haiyan; Li, Jian

doi:10.1021/acschemneuro.8b00014

Cited by 21 publications

(12 citation statements)

References 32 publications

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“…With a clearer understanding of the etiology and pathology of AD, many more new targets or key pathological features relevant to AD have been considered in recent years for producing effective MTDLs, such as phosphodiesterase type 5 (PDE5), sigma 1 receptor, inflammation, oxidative stress, etc. Considering the recently discovered critical roles of PDE5 against AD pathogenesis, a series of tadalafil derivatives were developed with dual-inhibition AChE and PDE5. , These derivatives had the properties of improved BBB permeability and AChE inhibitory activities compared to those of tadalafil, with the PDE5 inhibitory effect maintained. The representative compound 7 significantly inhibited AChE activity, enhanced the phosphorylation of CREB ex vivo , and alleviated the cognitive impairment induced by scopolamine in vivo .…”

Section: Discovery Of Ache Inhibition-based Multitarget Agents Agains...mentioning

confidence: 99%

“…Considering the recently discovered critical roles of PDE5 against AD pathogenesis, 129 a series of tadalafil derivatives were developed with dual-inhibition AChE and PDE5. 130,131 These derivatives had the properties of improved BBB permeability and AChE inhibitory activities compared to those of tadalafil, with the PDE5 inhibitory effect maintained. The representative compound 7 significantly inhibited AChE activity, enhanced the phosphorylation of CREB ex vivo, and alleviated the cognitive impairment induced by scopolamine in vivo.…”

Section: ■ Discovery Of Ache Inhibition-based Multitarget Agents Agai...mentioning

confidence: 99%

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Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer’s Disease

Wang

Zhang

2018

ACS Chem. Neurosci.

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106

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Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease-modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence, a lack of persistent treatment, and inappropriate medication times or doses. Here we pinpoint several topics fit for future attention, focusing on the updated cholinergic hypothesis, especially the pleiotropic relationships with key pathogenetic signaling pathways and functions in AD, as well as possible novel therapeutic strategies, including novel ChEIs and cholinesterase inhibition-based innovative multifunctional therapeutic candidates. We intend to strengthen the future value of the precise application of cholinergic drugs, especially novel ChEIs, as a cornerstone pharmacological approach to AD treatment, either alone or in combination with other targets, to relieve symptoms and to modify disease progression.

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Section: Discovery Of Ache Inhibition-based Multitarget Agents Agains...mentioning

confidence: 99%

Section: ■ Discovery Of Ache Inhibition-based Multitarget Agents Agai...mentioning

confidence: 99%

Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer’s Disease

Wang

Zhang

2018

ACS Chem. Neurosci.

Self Cite

106

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“…In addition, 141 exhibited an enhancement of central CREB protein phosphorylation, thereby potentially contributing to an amelioration of scopolamine-induced cognitive impairment in mice, and revealing a promising profile as an anti-AD, multitarget drug candidate. 175 Targeting AChE/BuChE and NMDA. The combination of donepezil, an AChE inhibitor, and memantine, the only marketed NMDA antagonist, is now a commonly used treatment for moderate to severe AD that has demonstrated beneficial effects.…”

Section: ■ Histone Deacetylase (Hdac) Inhibitorsmentioning

confidence: 99%

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

et al. 2021

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The natural β-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid β (Aβ), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure−activity relationship studies, the β-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the β-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.

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“…The lead compound ( 42 ) demonstrated significant memory‐enhancing effects in AD mouse model (Mao et al, ). However, compound ( 42 ) was nearly insoluble in water and was then further optimized to produce a series of more water‐soluble analogues ( 43 ) (Ni et al, ).…”

Section: Therapeutic Potential Of Tadalafil and Its Analogues In Med mentioning

confidence: 99%

Tadalafil: 15 years' journey in male erectile dysfunction and beyond

Ahmed¹

2018

Drug Development Research

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Tadalafil, Cialis, Eli Lilly & Co./ICOS, (6R,12aR)‐6‐(1,3‐benzodioxol‐5‐yl)‐2‐methyl‐2,3,6,7,12,12a‐hexahydropyrazino[1′,2′:1,6] pyrido[3,4‐b]indole‐1,4‐dione, was first discovered in 2003. It was reported to have high diastereospecificity for phosphodiesterase 5 (PDE5) inhibitions. The cis‐(6R, 12aR) enantiomer is the most active enantiomer. Tadalafil showed PDE5 inhibition with IC50 = 5 nM. It possesses high selectivity for PDE5 versus PDE1‐4 and PDE6. Tadalafil is more selective to PDE5 against PDE6 whereas sildenafil, another commercially available PDE5 inhibitor shows similar potencies to inhibit PDE5 and PDE6. Tadalafil is used for the treatment of male erectile dysfunction (MED), prostatic benign hyperplasia (PBH) signs and symptoms, and pulmonary arterial hypertension (PAH). Adcirca, another name for tadalafil, is used to treat PAH and improve exercise capacity. Recent clinical studies suggest the use of tadalafil for nonurological applications, including circulatory disorders (ischemia injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy, heart failure, and stroke), neurodegenerative disorders, and cognitive impairment conditions. This review discusses tadalafil and its analogues reported in the past 15 years. It discusses synthetic pathways, structural activity relationships, existing and future pharmacological indications of tadalafil and its analogues. This work can help medicinal chemists developing novel PDE5 inhibitors with wider therapeutic indications.

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Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5)

Cited by 21 publications

References 32 publications

Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer’s Disease

Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer’s Disease

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

Tadalafil: 15 years' journey in male erectile dysfunction and beyond

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