Endomorphin Analogs

Abstract

Opiate alkaloids, such as morphine, are powerful analgesic agents that are the drugs of choice for the treatment of severe pain. The pharmacological effects of opiates are mediated through the binding and activation of membrane-bound opioid receptors that are found in the central and peripheral nervous systems. Opioid receptors have been classified into three different types, mu, delta and kappa, and are activated by the specific ligands. It has been demonstrated that the most potent antinociceptive effects are mediated by the mu-receptor. However, until 1997 no endogenous ligand for this receptor was known. The identification of endomorphins opened a new era in the research of the mu-opioid system. They are the first reported brain peptides that label mu-receptor with high affinity and selectivity and therefore are proposed as the endogenous mu-opioid receptor ligands. Morphine and endomorphins act as agonists at the same mu-opioid receptor, but the latter are thought to inhibit pain without some of the undesired side-effects of plant opiates. This observation encouraged extensive studies on the possible use of endomorphin analogs as analgesics instead of morphine. This review summarizes a decade of research on structure-activity relationship studies of endomorphin analogs, aimed at obtaining compounds with increased bioavailability, in particular with better barrier penetration and resistance against enzymatic degradation. Chemical modifications that led to obtaining potent and selective agonists and antagonists based on the structure of endomorphins are discussed.

Cyclic Endomorphin Analogs in Targeting Opioid Receptors to Achieve Pain Relief

“…These unfavorable pharmacological properties have hindered the development of EMs for clinical use. To overcome the limited access of exogenously administered EMs to the brain and to search for analogs with minimal side-effects, numerous chemical modifications of their structure have been proposed [30][31][32][33].…”

Synthesis and Biological Activity of Endomorphin‐2 Analogs Incorporating Piperidine‐2‐, 3‐ or 4‐Carboxylic Acids Instead of Proline in Position 2

“…In efforts to develop new candidate drugs with antinociceptive activity, numerous chemical modifications have been performed to improve the pharmacological profile of endomorphins (2). Proline in position 2 of endomorphins is a spacer residue (3), connecting two pharmacophoric aromatic residues, Tyr 1 and Trp/Phe 3 .…”

Structure–activity relationships of modified C-terminal endomorphin-2 analogues by molecular dynamics simulations

“…Moreover, the amino acid, Phe 4 , is free to adopt a bioactive conformation that is independent of the other amino acids [11]. These results further point out the importance of the orientation of the C-terminal aromatic side chain for binding affinity to the MOR, indicating different structural features for each residues would influence the SARs and further affect the affinity and selectivity to MOR strongly [12].…”

“…As for conformational properties on modifications at C-terminus, a series of hydrophobic non-aromatic residues for Phe 4 by substitution of the C-terminal amide group has been studied [10]. Furthermore, it has been found that the (R) chiral center of the fourth amino acid may induce a proper spatial arrangement of the third aromatic ring of endomorphin analogues [12]. Hence, not only pharmacophoric residues, but also the Cterminal residue plays a critical role in the biological activity of the endomorphins.…”