Redoubling the ring size of an endomorphin‐2 analog transforms a centrally acting mu‐opioid receptor agonist into a pure peripheral analgesic

Abstract

The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-d-Lys-Phe-Phe-AspNH2 . The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer (Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 )2 2 showed a significant mixed mu/kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclopeptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood-brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 309-317, 2016.

Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208)

“…Albeit accompanied by severe side effects, MOR agonists are still the most potent and widely used analgesics. For this reason, on prosecuting a program dedicated to the discovery of new opioid peptides showing analgesic activity in vivo, ,,,, we turned our attention to the potent and selective MOR agonist 9 . Preliminarily, incubation in mouse serum for 3 h (Supporting Information) allowed confirming the enzymatic stability of 9 , as generally observed for bioactive cyclopeptides, , including 1 and 3 . , Subsequently, the peripheral preempitive antinociceptive effect elicited by 9 was determined in a mouse model of visceral pain, as previously reported .…”

A Brief Survey on Recent Endomorphin-1 and Endomorphin-2 Analogues

“…NorCal Open Access Publications Journal of Biochemistry and Chemical Sciences Volume 1; Issue 1 De Marco R [12,13] [14] [14] [15] [15] [16] H-Tyr-Sar-Phe-PheNH 2 [17,18] [ 17,18] [ [19][20][21][22] [c[Tyr-D-Pro-D-Trp-Phe-Gly [19,21,22] [c[Tyr-Gly-D-Trp-Phe-Gly [23] Ac-D-Trp-Phe-GlyNH 2 [24] Ac-5-NO 2 -D-Trp-Phe-GlyNH 2 [24] Ac-7-Br-2-Me-D-Trp-Phe-GlyNH 2 [25] H-Tyr-Pro-Phe-D-Val-NH 2 [26] [27] H-Tyr-Pro-Phe-PheNHNH 2 [27] H-Tyr-Pro-Trp-PheNHNH 2 [28] 27 [28] 28 [29] 29 [30] 30 [30] H-Tyr-Pro-Trp-(2R,3R)βMe-PheNH 2 31 [30] H-Tyr-Pro-Trp-(2S,3S)βMe-PheNH 2 32 [31] 33 [32] [C8Laa-Dmt]-Pro-Trp-PheNH 2 34 [33] 35 [34][35][36] 36 [37] Tyr-c[D-Lys-Phe-Phe-Asp]NH 2 37 [38] (Tyr-c[D-Lys-Phe-Phe-Asp]NH 2 ) 2 38 J Biochem Chem Sci 2017: 14-23.…”

“…DOI: https://doi.org/10.29199/BCCS.101012. [39] 39 [38] 40 [40] c[β-Ala-D-Pro-Phe-Trp] 41 [40] c[GABA-D-Pro-Phe-Trp] 42 The endomorphins have been deeply studied to developing drugs for the treatment of pain in humans [6,41]. The increasing interest encourages the development of modern green chemistry protocols for the production of large quantities of EMs [42][43][44].…”

“…administration [37]. Instead, the dimer of 37 (Tyr-c[D-Lys-Phe-Phe-Asp]NH 2 ) 2 (Table 1, 38) displayed a potent peripheral antinociceptive activity in the mouse model of visceral inflammatory pain [38], possibly associated to the larger molecular size which prevented the access into the CNS.…”

Ring Size as an Independent Variable in Cyclooligomeric Depsipeptide Antiarrhythmic Activity

“…Examples of the synthesis of non-natural analogues of cyclic depsipeptides include decabassianolide (analogue of bassianolide), a 12-mer and 24-mer of beauvericin, a tetradepsipeptide and cyclohexadepsipeptide analogue of valinomycin, and a 12-mer of bassianolide . More generally, there has been noteworthy work with the synthesis of ring-size analogues in the field of oligolides , as well as cyclic peptides. − Yet, still absent from most studies is a large range (>3-mer) of ring sizes, other structural functionality left unchanged, or the evaluation of these compounds against a distinct biological target.…”