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-2 receptor antagonist, emerged as the most potent competitive PAOX inhibitor known so far (K-i=10nM), endowed with very good selectivity compared with SMOX (K-i=1.2M 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.

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

Rosini, Michela;Milelli, Andrea;Basagni, Filippo;Minarini, Anna
2019

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 M-2 receptor antagonist, emerged as the most potent competitive PAOX inhibitor known so far (K-i=10nM), endowed with very good selectivity compared with SMOX (K-i=1.2M 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.
Di Paolo, Maria Luisa; Cervelli, Manuela; Mariottini, Paolo; Leonetti, Alessia; Polticelli, Fabio; Rosini, Michela; Milelli, Andrea; Basagni, Filippo; Venerando, Rina; Agostinelli, Enzo; Minarini, Anna
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/687297
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