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

Attila Borics, Jayapal R. Mallareddy, István Timári, K. Kövér, Attila Keresztes, Géza Tóth

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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)ΔAcpc 2-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.

Original languageEnglish
Pages (from-to)8418-8428
Number of pages11
JournalJournal of Medicinal Chemistry
Volume55
Issue number19
DOIs
Publication statusPublished - Oct 11 2012

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Carboxylic Acids
Pharmacology
Hydroxyproline
Opioid Receptors
Molecular Dynamics Simulation
Proteolysis
Central Nervous System
Ligands
Amino Acids
Pain
endomorphin 2

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

The effect of Pro2 modifications on the structural and pharmacological properties of endomorphin-2. / Borics, Attila; Mallareddy, Jayapal R.; Timári, István; Kövér, K.; Keresztes, Attila; Tóth, Géza.

In: Journal of Medicinal Chemistry, Vol. 55, No. 19, 11.10.2012, p. 8418-8428.

Research output: Contribution to journalArticle

Borics, Attila ; Mallareddy, Jayapal R. ; Timári, István ; Kövér, K. ; Keresztes, Attila ; Tóth, Géza. / The effect of Pro2 modifications on the structural and pharmacological properties of endomorphin-2. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 19. pp. 8418-8428.
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