Conformationally Restricted Peptides as Tools in Opioid Receptor Studies

Abstract

The discovery of endogenous opioid peptides with their limited receptor selectivity more than two decades ago implicated their involvement in analgesia and initiated efforts to understand the molecular mechanisms underlying their action. Opioid peptides mediate their physiological and pharmacological effects through three major opioid receptor types (mu, delta, kappa), but the role of each of these receptors is not easy to distinguish. There has therefore, been an increasing need for potent and selective agonists and antagonists in this area. The incorporation of conformational constraints into analogs of biologically active peptides is a well-known approach for enhancing receptor selectivity and modulating efficacy. Conformational restriction has proven a valuable means for assessing disparities between the peptide binding characteristics at each of the opioid receptor types, since peptide analogs designed with appropriate conformational constraints possess the ability to adopt the conformation required for interaction at one receptor type but not another. In efforts to obtain better conformational integrity various conformationally restricted analogs of endogenous opioid peptides have been developed. In this paper we review the development of opioid analogs whose conformation was restricted either globally through different types of cyclization (such as amide bond formation, disulfide and monosulfide bridges, carbonyl and amine bridges) or locally, through incorporation of side-chain conformational constraints at a specific amino acid residue by synthesizing cyclic amino acids or constraining torsion angles by suitable substitutions. These two approaches have led to the development of potent and very selective agonists and antagonists at all three opioid receptor types.

The Endomorphin System and Its Evolving Neurophysiological Role

“…For more data on endomorphin analogs, please refer to the articles by Janecka et al (2004), Gentilucci and Tolomelli (2004), and Janecka and Kruszynski (2005).…”

Structural comparison of μ-opioid receptor selective peptides confirmed four parameters of bioactivity

“…Because of their short in vivo half-life [14] exogenous application of synthetic neuropeptides to suppress chronic pain is greatly limited. To increase stability against proteases while maintaining opioid activity, hundreds of synthetic analogues of EM-1 and EM-2 were prepared by inserting non-natural amino acid residues [15][16][17][18][19][20][21][22][23][24][25], introducing conformational constraints [26][27][28][29], modifying peptide bonds [30] and by designing stereoisomers [31] or peptidomimetics [32][33][34].…”

“…The solution structure of EMs and their analogues, in relation with their bioactivity, was investigated extensively and the results were summarized in excellent reviews [29,40], but the backbone and side-chain conformation responsible for the m-opioid activity of EM-1 and EM-2 is still debated. There is no agreement about whether peptides bind to the MOR in an extended- [41,43] or in a more compact, bent [25,26,32] backbone structure, since both conformational families are readily accessible for EMs and other short opioid peptides in solution [43,44,45].…”

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

“…Nevertheless, the conformation of the main chain positions the side chains in a defined spatial positions, which allow optimal interactions with the enzyme or receptor proteins, and the amide bonds themselves may also be of importance for binding activity. 24,27 The conformation of EMs in their bioactive form is a controversial issue too. Earlier, the transconformer, which is present in higher portion in the cis/trans-equilibrium, was concluded to be the bioactive conformer, 78 and later, the cis-conformer was also directly evidenced to be the bioactive conformer.…”