Cyclic Endomorphin Analogs in Targeting Opioid Receptors to Achieve Pain Relief

Abstract

Endomorphins, the endogenous ligands of the µ-opioid receptor, are attractive candidates for opioid-based pain-relieving agents. These tetrapeptides, with their remarkable affinity for the µ-opioid receptor, display favorable antinociceptive activity when injected directly into the brain of experimental animals. However, the application of endomorphins as clinical analgesics has been impeded by their instability in body fluids and inability to reach the brain after systemic administration. Among numerous modifications of the endomorphin structure aimed at improving their pharmacological properties, cyclization can be viewed as an interesting option. Here, we have summarized recent advances in obtaining endomorphin-based cyclic peptide analogs.

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

“…As expected, both analogues 5 and 6 greatly increased the μ-, δand κ-opioid affinities compared with analogues 3 and 4, and establishing the replacement of the Tyr 1 residue in EM analogues by Dmt 1 paved the way for achieving high opioid affinity. 32,33 Moreover, analogues 5 and 6 displayed relatively higher pharmacological potencies in GPI and MVD preparations, consistent with their binding affinities. Therefore, multiple chemical modifications of EMs with Dmt 1 substitution, cyclization, chloro-halogenation at the Phe 4 paraposition, and C-terminal oligoarginine conjugation gave an efficient strategy to obtain potent novel analogues.…”

Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

“…Although there is a strong evidence for their role in pain regulation and potential use as analgesics, their poor enzymatic stability and difficulties in penetrating the blood–brain barrier (BBB) after systemic administration have limited their clinical applicability [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Generation of potent, stable peptidomimetics with improved pharmacodynamics and pharmacokinetics entails a systematic understanding of the structure-activity relationships (SAR), where the function of key residues can be determined using different strategies, such as amino acid substitution, deletion or addition of natural or unnatural amino acids, conformational restriction through peptide main chain or side chain cyclization, peptide bond replacement, or design of bi- or multifunctional peptide ligands [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. A diversity of opioid peptide-based analgesics with reduced adverse effects was made available through chemical synthesis and appraised as prospective therapeutic agents or research tools [ 5 , 11 , 13 , 14 , 15 , 17 ].…”

Decarboxylative Peptide Macrocyclization through Photoredox Catalysis

“…At the heart of this focus is the remarkable finding that this class of peptide structure delivers unprecedented and selective therapeutic benefit for a large range of disease areas that include oncology, algiatry, and neurology. [1] While many naturally occurring macrocycles have found medicinal applications over the last century, the use of non-natural cyclic peptides has become prominent due mainly to the advent of synthetic biology technologies that allow large numbers of these macrocyclic rings to be rapidly assembled and tested on micro scale. [2] …”