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. 2019 Dec;34(1):740-752. doi: 10.1080/14756366.2019.1584620.

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.

Keywords: Polyamine analogues; docking studies; inhibitors; polyamine oxidase; spermine oxidase.

MeSH terms

  • Diamines / chemical synthesis
  • Diamines / chemistry
  • Diamines / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Oxidoreductases Acting on CH-NH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Polyamine Oxidase
  • Polyamines / chemical synthesis
  • Polyamines / chemistry
  • Polyamines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Diamines
  • Enzyme Inhibitors
  • Polyamines
  • Oxidoreductases Acting on CH-NH Group Donors
  • methoctramine

Grants and 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).