Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Abstract

The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

The improved blood–brain barrier permeability of endomorphin-1 using the cell-penetrating peptide synB3 with three different linkages

“…As we know, peptide and protein drugs hold great promise for the treatment of brain disorders (Hökfelt et al, 2003;Liu and Wang, 2012;Selkoe, 2001). Nevertheless, their poor transfer through the BBB leads, typically, to failure to reach the target after systemic administration.…”

Endomorphin-1 analogues (MELs) penetrate the blood–brain barrier and exhibit good analgesic effects with minimal side effects

“…Compared with the Phe 4 in the parent peptide, both the aromatic group and the backbone structure of Map were highly constrained, and this limitation of the conformational flexibility could be regarded as an efficient strategy for BBB permeability (Keresztes et al, 2010;Guillemyn et al, 2012). In addition, the improved CNS penetrating efficacy of EM-1 has previously been achieved by second-site or multiple-site modifications (Keresztes et al, 2010;Liu and Wang, 2012), and our study indicated that the C-terminus is another potential site to regulate the BBB permeability of EM-1.…”

“…However, the inability of EM-1 to pass through the BBB has greatly hampered its clinical development (Tomboly et al, 2002;Janecka et al, 2008;Liu and Wang, 2012). In our previous study, we described a series of EM-1 analogues (termed MELs) obtained by chemical modifications that showed improved in vitro characteristics as compared to the parent peptide Liu et al, 2013).…”

“…The rewarding behavior of EMs could be separated from their antinociception (Wilson et al, 2000), and they are less prone to induce cardiovascular disorders and respiratory depression (Czapla et al, 2000). However, the clinical development of EMs has been hampered by their poor metabolic stability and limited ability to penetrate the bloodÀbrain barrier (BBB) (Mentlein, 1999;Shane et al, 1999;Tomboly et al, 2002;Liu and Wang, 2012). A major limitation to the use of EMs as painkillers is their low stability against enzymatic degradation.…”

Opioid Receptors in Pain Management: Past, Present and Future

“…8 In 1997, highly selective m-peptides, termed endomorphins, were added to the roster of endogenous ligands. [9][10][11] Opioid receptors belong to the family of metabotropic membrane receptors that couple via the Gi/Go subtypes of G proteins to cellular transduction processes. The opioid receptors are widely distributed throughout the body; those involved in pain modulation are found in the central nervous system and the peripheral nervous system; opioid receptors are also found on cells of the immune system, [12][13][14] throughout the enteric nervous system of the gastrointestinal tract 15 and elsewhere.…”