N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual Inhibitor

Aguilera, Óscar; Samadi, Abdelouahid; Chioua, Mourad; Nikolic, Katarina; Filipić, Slavica; Agbaba, Danica; Soriano, Elena; Andrés, Lucía de; Rodríguez‐Franco, María Isabel; Alcaro, Stefano; Ramsay, Rona R.; Ortuso, Francesco; Yáñez, Matilde; Marco‐Contelles, José

doi:10.1021/jm501501a

Cited by 58 publications

(44 citation statements)

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“…12, [18][19][20][21][22] As in the case of ASS234, each compound was individually tested by co-application with ACh to α7 nAChRs. As shown in Figure 3, a varied degree of inhibitory responses of ACh-induced currents was observed, whereas no significant potentiation was exerted by any of the tested compounds.…”

Section: Resultsmentioning

confidence: 99%

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

Criado

Mulet

Sala

et al. 2016

ACS Chem. Neurosci.

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Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for α7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca 2+ signals mediated mainly by α7 nAChRs.Finally, these compounds, especially 38 and 13, inhibited 5-HT 3A serotonin receptors whereas they had no effect on α1 glycine receptors.

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Section: Resultsmentioning

confidence: 99%

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

Criado

Mulet

Sala

et al. 2016

ACS Chem. Neurosci.

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“…With structures of most targets available, in silico screening is a useful tool for examining large chemical databases (Hughes et al, 2016; Nikolic et al, 2016). Combining known drugs for each target into one molecule has also produced promising compounds by incorporating elements of proven inhibitors for each target into new multi-potent molecules (Bolognesi et al, 2007; Piazzi et al, 2008; Zhu et al, 2009; Kupershmidt et al, 2012; Luo et al, 2013; Sun et al, 2014; Bautista-Aguilera et al, 2014b; Wang L. et al, 2014; Pisani et al, 2016; Weichert et al, 2016; Xie et al, 2016). One example that progressed to clinical trials against AD is ladostigil, designed to inhibit MAOs and ChEs but also incorporating potent anti-apoptotic and neuroprotective activities (Weinreb et al, 2012; Youdim, 2013).…”

Section: Addressing the Pathology Of Neurodegeneration: The Targets Cmentioning

confidence: 99%

“…During biological assessment, it became apparent that this compound has neuroprotective properties, by inhibiting Aβ42 and Aβ40 self-aggregation into plaques, and by protecting against depletion of antioxidative enzymes (Bolea et al, 2013). Therefore ASS234 has been patented (PCT/ES070186; WO2011/113988 A1) as a promising compound for the treatment of AD.Many other ChE/MAO targeted MTDL have been designed in the last 5 years, either propargyl-based (Youdim, 2013; Bautista-Aguilera et al, 2014b; Samadi et al, 2015; Weinreb et al, 2015) or coumarins derivatives (Pisani et al, 2011; Patil et al, 2013; Farina et al, 2015; Xie et al, 2015). The challenge will be to add further neuroprotective properties to progress to a disease-modifying drug.…”

Section: Neurotransmitter Degrading Enzymesmentioning

confidence: 99%

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

et al. 2016

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HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases.Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to “dirty drugs” for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress toward strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent met...

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“…Therefore, multipotent brain permeable drugs affecting few brain targets involved in the disease pathology, such as MAO and ChE enzymes, Aβ generation/aggregation and iron accumulations were extensively studied as essential therapeutic approach in treatment of AD [28,[34][35][36][37][38][39][40][41][42][43]." Quantitative Structure Activity Relationship (QSAR) modeling and related cheminformatic methods are developed and applied in helping to guide computer-aideddrug-design (CADD) [44,45] and in polypharmacology for design of ligands with unique polypharmacological profiles [8,46].…”

Section: Polypharmacologymentioning

confidence: 99%

“…For example, the MAO A/B and AChE/BuChE inhibiting activities of multitarget donepezil and tacrine hybrids [35,38,39,40,42,43,47] were used in our recent 3D-QSAR and ASS234 optimisation studies [36,37]. [33].…”

Section: Polypharmacologymentioning

confidence: 99%

Polypharmacology of dopamine D1-like receptor antagonists

Nikolic¹,

Filipić²,

Agbaba³

2015

Arh farmaciju

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Drug discovery based on development of selective ligands for a specific target intended to modulate its activity and revert pathophysiological process is now recognized as too simplistic to design effective agent for complex multifactorial diseases, characterized by diverse physiological dysfunctions caused by deregulations of complex networks of proteins. Major challenge in modern drug discovery is to rationally design multitarget drugs able to specifically modulate only a group of desired targets while minimizing interactions with off-targets. Multifactorial cerebral mechanisms implicated in mental (psychiatrics) and neurodegenerative diseases and interactions of the neurotransmitter systems are two main reasons for applying polypharmacology ("multi-target") strategy in drug discovery for these complex brain diseases. In this paper we review polypharmacological profile and potential therapeutic application of dopamine D 1 -like receptor antagonists.

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N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual Inhibitor

Cited by 58 publications

References 58 publications

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

Polypharmacology of dopamine D1-like receptor antagonists

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