On resin click-chemistry-mediated synthesis of novel enkephalin analogues with potent anti-nociceptive activity

Azzurra Stefanucci,John M Streicher,Wei Lei,Ettore Novellino,Francesca Marzoli,Stefano Pieretti,Marilisa Pia Dimmito,Adriano Mollica

doi:10.1038/s41598-019-42289-5

Azzurra Stefanucci, John M Streicher + Show 6 more

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https://doi.org/10.1038/s41598-019-42289-5

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Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This entailed the solid-phase synthesis of two enkephalin precursor chains followed by a CuI-catalyzed azide-alkyne cycloaddition, with the aim of improving in vivo analgesic efficacy versus DPDPE. NOVA2 showed good affinity and selectivity for the μ-opioid receptor (KI of 59.2 nM, EC50 of 12.9 nM, EMax of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.

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DPDPE ((D-Pen2,D-Pen5)-Enkephalin) represents one of the most successful designed cyclic opioid peptides
Cyclic peptidomimetics are usually characterized by: (i) folding in a rigid structure[13]; (ii) an improved metabolic stability compared to the linear counterparts[14]; (iii) better penetration of the blood-brain barrier (BBB)[15]; (iv) improved oral bioavailability and rapid excretion[16]; (v) and a better pharmacological profile in terms of potency and selectivity[17]
In comparison to previously published DPDPE analogues incorporating the xylene moiety[26], our modifications provided a balanced profile and selectivity for the MOP and DOP, while demonstrating very little KOP binding. These findings provide further SAR information relating to our compound modifications to the cyclic enkephalin structures

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DPDPE ((D-Pen2,D-Pen5)-Enkephalin) represents one of the most successful designed cyclic opioid peptides. Cyclic peptidomimetics are usually characterized by: (i) folding in a rigid structure[13]; (ii) an improved metabolic stability compared to the linear counterparts[14]; (iii) better penetration of the blood-brain barrier (BBB)[15]; (iv) improved oral bioavailability and rapid excretion[16]; (v) and a better pharmacological profile in terms of potency and selectivity[17] These features could make DPDPE and other analogues good candidates as leads for drug development, as peptides are generally characterized by high selectivity and low toxicity[18]. The 18-membered enkephalin (ENK) analogue cyclo(Nε,Nβ’-carbonyl-D-Lys2,Dap5)-enkephalinamide was obtained performing the on-resin cyclization reaction between the unprotected side chains of D-Lys and Dap with bis-(4-nitrophenyl)carbonate in the linear peptide sequence, to incorporate the urea moiety[19] This compound showed high MOP and DOP agonist activities (IC50 = 0.21 and 0.65 nM in the GPI and MVD assay, respectively) compared to Leu-ENK, without exhibiting substantial selectivity[19,20]. The N-ureidoethylamides Tyr-c2,4[DLys-Phe-Dab]-CH2CH2NHCONH2 showed a stronger antinociceptive response than that of morphine and was resistant to enzymatic degradation[24]

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