Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase.
J Enzyme Inhib Med Chem
; 34(1): 740-752, 2019 Dec.
Article
em En
| MEDLINE
| ID: mdl-30829081
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 µM 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Poliaminas
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Diaminas
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Inibidores Enzimáticos
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Oxirredutases atuantes sobre Doadores de Grupo CH-NH
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article