The effect of Pro2 modifications on the structural and pharmacol

The effect of Pro2 modifications on the structural and pharmacological properties of endomorphin-2.

A. Borics , J. R. Mallareddy , I. Timári , K. E. Kövér , A. Keresztes , G. Tóth,
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/jm300836n
Publication Date (Web): September 10, 2012
Copyright © 2012 American Chemical Society

Endomorphins (EM-1 and EM-2) are selective, high affinity agonists of the μ-opioid (MOP) receptor, an important target in pain regulation. Their clinical use is impeded by their poor metabolic stability and limited entry to the central nervous system. In this study the Pro2 residue of EM-2 was modified systematically through substitution by hydroxyproline (Hyp), (S)-β-homoproline (βPro), 2-aminocyclopentene-1-carboxylic acid (ΔAcpc) or 2-aminocyclohexene-1-carboxylic acid (ΔAchc) to obtain stable MOP active compounds. Both Hyp2 and βPro2 substitution decreased receptor affinity. Analogues incorporating alicyclic β-amino acids exhibited diverse receptor binding properties, depending on the configuration of the substituent side-chain. (1S,2R)ΔAcpc2-EM-2 was shown to have MOP affinity and selectivity comparable to those of EM-2 and proved to act as agonist, while being resistant to proteolysis. NMR and molecular dynamics (MD) studies revealed that bent backbone structures are predominant in the most potent analogues, while their presence is less pronounced in ligands of lower receptor affinity.