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 (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.

Keywords:

• Polyamine analogues
• docking studies
• spermine oxidase
• polyamine oxidase
• inhibitors

Acknowledgements

The authors thank the “International Polyamine Foundation - ONLUS” for the availability to look up in the Polyamine documentation. Dr. Andrea Pasquadibisceglie is gratefully acknowledged for his contribution to docking studies.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by institutional grants from the University of Padova, Italy (Fondi di ricerca di Ateneo, Ex 60% 2015, code 60A06-1707/15) to M.L.D.P. and from the University of Bologna, Italy (RFO 2015–2016) to A.M. (Anna Minarini).