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Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase.


ABSTRACT: Fourteen polyamine analogues, asymmetric or symmetric substituted spermine (1-9) or methoctramine (10-14) analogues, were evaluated as potential inhibitors or substrates of two enzymes of the polyamine catabolic pathway, spermine oxidase (SMOX) and acetylpolyamine oxidase (PAOX). Compound 2 turned out to be the best substrate for PAOX, having the highest affinity and catalytic efficiency with respect to its physiological substrates. Methoctramine (10), a well-known muscarinic M2 receptor antagonist, emerged as the most potent competitive PAOX inhibitor known so far (Ki?=?10?nM), endowed with very good selectivity compared with SMOX (Ki=1.2??M vs SMOX). The efficacy of methoctramine in inhibiting PAOX activity was confirmed in the HT22 cell line. Methoctramine is a very promising tool in the design of drugs targeting the polyamine catabolism pathway, both to understand the physio-pathological role of PAOX vs SMOX and for pharmacological applications, being the polyamine pathway involved in various pathologies.

SUBMITTER: Di Paolo ML 

PROVIDER: S-EPMC6407594 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase.

Di Paolo Maria Luisa ML   Cervelli Manuela M   Mariottini Paolo P   Leonetti Alessia A   Polticelli Fabio F   Rosini Michela M   Milelli Andrea A   Basagni Filippo F   Venerando Rina R   Agostinelli Enzo E   Minarini Anna A  

Journal of enzyme inhibition and medicinal chemistry 20191201 1


Fourteen polyamine analogues, asymmetric or symmetric substituted spermine (1-9) or methoctramine (10-14) analogues, were evaluated as potential inhibitors or substrates of two enzymes of the polyamine catabolic pathway, spermine oxidase (SMOX) and acetylpolyamine oxidase (PAOX). Compound 2 turned out to be the best substrate for PAOX, having the highest affinity and catalytic efficiency with respect to its physiological substrates. Methoctramine (10), a well-known muscarinic M<sub>2</sub> recep  ...[more]

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