Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase. (1st January 2019)

• Record Type: Journal Article
• Authors: Di Paolo, Maria Luisa; Cervelli, Manuela; Mariottini, Paolo; Leonetti, Alessia; Polticelli, Fabio; Rosini, Michela; Milelli, Andrea; Basagni, Filippo; Venerando, Rina; Agostinelli, Enzo; Minarini, Anna
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 740
• Page End: 752
• Publication Date: 2019-01-01
• Subjects: Polyamine analogues -- docking studies -- spermine oxidase -- polyamine oxidase -- inhibitors; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1584620
• Languages: English
• ISSNs: 1475-6366

Abstract

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 ( K i = 10 nM), endowed with very good selectivity compared with SMOX ( K i =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.