Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge

Abstract

d-Pen,d-Pen enkephalin (DPDPE) is one of the most selective synthetic peptide agonists targeting the δ-opioid receptor. Three cyclic analogues of DPDPE containing a xylene bridge in place of disulfide bond have been synthesized and fully characterized as opioid receptors agonists. The activity was investigated showing a good affinity of- for μ- and δ-receptors. biological assays revealed that is the most potent analogue with the ability to maintain high level of analgesia from 15 to 60 min following intracerebroventricular (i.c.v.) administration, whereas DPDPE was slightly active until 45 min. Compound induced long lasting analgesia also after subcutaneous administration, whereas DPDPE was inactive.

Design, synthesis and biological profile of mixed opioid agonist/N-VGCC blocker peptides

“…The same pattern was found for the blocking activity toward Cav2.2 when compared to ziconotide. [22][23][24][25] However, it is worth noting that the improvement of the antinociceptive effect recorded for compound 5a compared with that previously reported for compound 10 in the tail flick test, (Figure 4), may be either related to a higher potency to the Cav2.2 and/or to better tissue penetration and pharmacokinetic. Indeed, the calcium channel blocker activity of 5a is 200 times higher than that of compound 10.…”

Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists

“…Description of the reaction procedures [22][23][24] and compounds characterization are reported in detail in the Supplementary Materials.…”

“…Taking this in mind, we focused our attention on the functionalization of kyna via a variant of Steglich esterification with the previously prepared Boc-protected 2-aminoethanol [23] so as to obtain intermediate 2 in 60% yield after purification by column chromatography (see General Procedure) [24]. Compound 2 was deprotected with a mixture of TFA:DCM = 1:1 at r.t. for 1 h and the so obtained intermediate was coupled with Boc-N(Me)Phe-OH, following the standard procedure for coupling reaction [36].…”

“…Finally, linear peptides K4-K6 have been synthesized as methyl ester, acid, and amide derivatives, respectively, starting from L-kyn methyl ester 15 (Scheme 3), prepared following the procedure described in the literature [24,36]. [24]. Boc group removal of the linear peptides 20 and 21 afforded products K5 and K6 in good yields (72% and 52%, respectively), and excellent purity after RP-HPLC purification (98% and 96%, respectively).…”

“…Boc group removal of the linear peptides 20 and 21 afforded products K5 and K6 in good yields (72% and 52%, respectively), and excellent purity after RP-HPLC purification (98% and 96%, respectively). Finally, linear peptides K4-K6 have been synthesized as methyl ester, acid, and amide derivatives, respectively, starting from L-kyn methyl ester 15 (Scheme 3), prepared following the procedure described in the literature [24,36]. [24].…”