Delta opioid agonists: a concise update on potential therapeutic applications

Abstract

SUMMARYWhat is known and objective: The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators -thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes (PNOC, PENK, PDYN and POMC) are the pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-PheLeu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor (DOR). We present a concise update on the status of progress and opportunities of this approach. Methods: A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from www.clinicaltrials.com. Results and discussion: DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. What is new and conclusion: Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others. WHAT IS KNOWN AND OBJECTIVE

Satb2 determines miRNA expression and long-term memory in the adult central nervous system

“…RNA-seq analysis identified a number of protein-coding genes that were differentially expressed between control and Satb2 cKO mice (25 up-regulated and 15 down-regulated, Figure 6—source data 1). Amongst them we found genes that have previously been identified as highly relevant for learning and memory or directly implicated in memory formation such as Adra2a , Penk , Htr5b , and Ghsr (Diano et al, 2006; Galeotti et al, 2004; Ghersi et al, 2015; Peppin and Raffa, 2015). Pathway analysis revealed significant enrichment (p=0.018) of the ‘neuroactive ligand-receptor interaction pathway’ amongst the regulated genes.…”

Synthesis and Opioid Activity of Tyr1‐ψ[(Z)CF=CH]‐Gly2 and Tyr1‐ψ[(S)/(R)‐CF3CH‐NH]‐Gly2 Leu‐enkephalin Fluorinated Peptidomimetics

“…Further, administration of DOPR agonists in combination with MOPR agonists may enable lower dosing of the latter . Thus, DOPR agonists have potential to treat chronic and acute pain with minimal side effects …”

“…[18][19][20][21] Thus, DOPR agonists have potential to treat chronic and acute pain with minimal side effects. [22] Endogenous peptides activateo pioid receptors, and are therefore promising leads for developingt herapeutic candidates for managing pain. [23] One such peptide, Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), acts by interacting with DOPR (1-5-fold binding affinity over MOPR and > 1000-fold over KOPR).…”

“…[54] Removal of the tert-butanesulfinyl group with hydrochloric acid in methanola tr eflux gave amine (S,S)-20, [54] which was alkylated with ethyl bromoacetate to afford (S,S)-21, although the alkylation required harsh conditions (NaH, HMPA) due to the weak nucleophilicity of the trifluoroethylamine. [57] The saponification of (S,S)-21 with LiOH furnished the desired trifluoroethylamined ipeptide mimetic, Bn-Tyr 1 -y[(S)-CF 3 CH-NH]-Gly 2 (22). Finally,E DC mediated coupling of (S,S)-22 with tripeptide 15, [52,53] deprotection with LiOH and Pd(OH) 2 /C-H 2 , followed by HPLC purification gave (S)-7 in 37 %y ield and > 99 %UPLC purity (Scheme 2B).…”

“…Removal of the tertbutanesulfinyl group afforded amine( S,R)-20,a nd subsequent alkylation with ethyl bromoacetate provided (S,R)-21 (Scheme3A). [54,57] Saponificationo f( S,R)-21 provided desired dipeptide isostere, Bn-Tyr 1 -y[(R)-CF 3 CH-NH]-Gly 2 (22). Finally, EDC mediated coupling of (S,R)-22 with tripeptide 15, [52,53] de-protection,a nd HPLC purification provided (R)-8 in 25 %y ield and 99 %o verall purity (Scheme 3B).…”