Species Differences in the Selective Inhibition of Monoamine Oxidase (1-methyl-2-phenylethyl)hydrazine and its Potentiation by Cyanide

Ramadan, Zakia Ben; Wrang, Maria L.; Tipton, Keith F.

doi:10.1007/s11064-007-9309-x

Cited by 8 publications

(7 citation statements)

References 21 publications

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“…Alkylation at this position, which presumably hinders hydrazone formation, makes pheniprazine (1-methyl-2-phenylethylhydrazine) a 10-fold more potent inhibitor of bovine MAO compared to its non-methylated analoguephenelzine (Patek and Hellerman 1974). Even further enhancement of pheniprazine efficacy can be induced by cyanide which acts as an enhancer of binding (Ramadan et al 2007). With MAO A and MAO B from rat and ox liver, potassium cyanide decreased the Ki of pheniprazine 5-10-fold, but there were no observable differences in inactivation rates for either of the isoenzymes studied.…”

Section: Mechanism Of Inactivationmentioning

confidence: 98%

Kinetics, mechanism, and inhibition of monoamine oxidase

Ramsay

Albreht

2018

J Neural Transm

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Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital antidepressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help to maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer's disease, albeit not yet proven clinically. Vital information for inhibitor design comes from an understanding of the structure, mechanism, and kinetics of the catalyst. This review will summarize the kinetic behaviour of MAO A and B and the kinetic evaluation of reversible inhibitors that transiently decrease catalysis. Kinetic parameters and crystal structures have enabled computational approaches to ligand discovery and validation of hits by docking. Kinetics and a wide variety of substrates and inhibitors along with theoretical modelling have also contributed to proposed schemes for the still debated chemical mechanism of amine oxidation. However, most of the marketed MAO drugs are long-lasting irreversible inactivators. The mechanism of irreversible inhibition by hydrazine, cyclopropylamine, and propargylamine drugs will be discussed. The article finishes with some examples of the propargylamine moiety in multi-target ligand design to combat neurodegeneration.

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Section: Mechanism Of Inactivationmentioning

confidence: 98%

Kinetics, mechanism, and inhibition of monoamine oxidase

Ramsay

Albreht

2018

J Neural Transm

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“…In addition, the cyano group, which was only present in some derivatives, was found to enhance the binding to AChE, BuChE, and MAO A (Wang et al, 2014 ). Although α-aminonitriles have seldom been investigated as ChE inhibitors, some previous studies described nitriles as MAO inhibitors, and reported that cyanide potentiates irreversible MAO inhibition (Ramadan et al, 2007 ). Although cyanide is known to be a poor reversible inhibitor of the oxidation of benzylamine by MAO (Houslay and Tipton, 1973 ), previous studies have indicated that the inhibitory activity of several compounds against MAO is potentiated by cyanide (Davison, 1957 ; Ramadan and Tipton, 1998 ; Ramadan et al, 1999 , 2007 ; Juárez-Jiménez et al, 2014 ).…”

Section: Multi-target-directed Ligands (Mtdl)mentioning

confidence: 99%

“…Although α-aminonitriles have seldom been investigated as ChE inhibitors, some previous studies described nitriles as MAO inhibitors, and reported that cyanide potentiates irreversible MAO inhibition (Ramadan et al, 2007 ). Although cyanide is known to be a poor reversible inhibitor of the oxidation of benzylamine by MAO (Houslay and Tipton, 1973 ), previous studies have indicated that the inhibitory activity of several compounds against MAO is potentiated by cyanide (Davison, 1957 ; Ramadan and Tipton, 1998 ; Ramadan et al, 1999 , 2007 ; Juárez-Jiménez et al, 2014 ). An earlier study by Davison ( 1957 ) on the inhibition of mitochondrial MAO by the irreversible inhibitor iproniazid revealed that, although at low concentrations, this compound alone had little effect on enzyme activity, while the inhibitory activity was significantly enhanced in the presence of cyanide ions.…”

Section: Multi-target-directed Ligands (Mtdl)mentioning

confidence: 99%

Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease

et al. 2016

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HIGHLIGHTS• ASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.• Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1.• MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal-chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated.• The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III).• MTDL-4 showed higher affinity toward AChE, BuChE.• MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.• MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy.Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept ® ) but with limited therapeutic success. This might be due to the Unzeta et al.New MTDLs for Alzheimer's Disease complex multifactorial nature of AD, a fact that has prompted the design of new MultiTarget-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy.

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“…Comparison of the rat and human MAO structures revealed minor differences reflecting the reported species differences in substrate and inhibitor specificity (Krueger et al , 1995, Ramadan et al , 2007. In all structures, the catalytic FAD is at the end of a tunnel leading from the surface of the protein.…”

Section: Structures and Active Sitesmentioning

confidence: 92%

Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases

Ramsay¹

2019

Pharmaceutical Biocatalysis

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is modified by irreversible inhibitors 3. MAO proteins 3.1 MAO protein expression and turnover 3.2 MAO A and MAO B structures and active sites 3.3 MAO chemical mechanism 3.4 MAO kinetic mechanism: two-substrate kinetics 4. Substrate Specificity of these Promiscuous Enzymes 4.1 Neurotransmitter metabolism 4.2 Metabolism of biogenic amines 4.3 Products from MAO catalysis 5. Inhibition of MAO 5.1 Reversible inhibitors of MAO 5.2 Examples of tight binding reversible inhibitors of MAO 5.3 Examples of irreversible inhibitors of MAO 6. Computational innovation 6.1 Theoretical elucidation of mechanism 6.2 Data-mining and tools for drug discovery 7. Conclusion: the future for MAO inhibition in multi-target drugs

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Species Differences in the Selective Inhibition of Monoamine Oxidase (1-methyl-2-phenylethyl)hydrazine and its Potentiation by Cyanide

Cited by 8 publications

References 21 publications

Kinetics, mechanism, and inhibition of monoamine oxidase

Kinetics, mechanism, and inhibition of monoamine oxidase

Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease

Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases

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