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

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 Cu(I)-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 (K(I) of 59.2 nM, EC(50) of 12.9 nM, E(Max) of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.