Abstract
An innovative chemical strategy named peptide welding technology (PWT) has been developed for the facile synthesis of tetrabranched peptides. [Dmt1]N/OFQ(1–13)-NH2 acts as a universal agonist for nociceptin/orphanin FQ (N/OFQ) and classical opioid receptors. The present study investigated the pharmacological profile of the PWT derivative of [Dmt1]N/OFQ(1–13)NH2 (PWT2-[Dmt1]) in several assays in vitro and in vivo after spinal administration in monkeys subjected to the tail withdrawal assay. PWT2-[Dmt1] mimicked the effects of [Dmt1]N/OFQ(1–13)-NH2 displaying full agonist activity, similar affinity/potency and selectivity at human recombinant N/OFQ (NOP) and opioid receptors in receptor binding, stimulation of [35S]GTPγS binding, calcium mobilization in cells expressing chimeric G proteins, and BRET studies for measuring receptor/G-protein and receptor/β-arrestin 2 interaction. In vivo in monkeys PWT2-[Dmt1] elicited dose-dependent and robust antinociceptive effects being more potent and longer lasting than [Dmt1]N/OFQ(1–13)-NH2. The analgesic action of PWT2-[Dmt1] was sensitive to the NOP receptor antagonist J-113397, but not naltrexone. Thus, the present study demonstrated that the tetrabranched derivative of [Dmt1]N/OFQ(1–13)-NH2 obtained with the PWT technology maintains the in vitro pharmacological profile of the parent peptide but displays higher potency and longer lasting action in vivo.
Highlights
An innovative chemical strategy for the facile synthesis of tetrabranched peptide derivatives has been developed and named peptide welding technology (PWT) (Guerrini et al, 2014)
Purified [Dmt1Cys14]nociceptin/ orphanin FQ (N/OFQ)(1-14)-NH2 was reacted in solution with PWT2 core in a classical thio-Michael reaction using experimental conditions previously optimized for the synthesis of N/OFQ tetra branched derivatives (Rizzi et al, 2014)
PWT2-[Dmt1] showed an ~18 fold loss of affinity compared to its patent compound (Fig. 2C)
Summary
An innovative chemical strategy for the facile synthesis of tetrabranched peptide derivatives has been developed and named peptide welding technology (PWT) (Guerrini et al, 2014). The PWT has been applied to different peptide sequences including nociceptin/ orphanin FQ (N/OFQ) (Rizzi et al, 2014; Rizzi et al, 2015), neuropeptide S (Ruzza et al, 2015), and tachykinins (substance P, neurokinin A and B) (Ruzza et al, 2014). These studies demonstrated that PWT derivatives maintained the in vitro pharmacological profile (pharmacological activity, potency and selectivity of action) of the parent peptide sequences while showing higher in vivo potency and long lasting action. In vivo in the tail withdrawal assay in monkeys [Dmt1]N/OFQ(1-13)-NH2 given intrathecally (i.t.) elicited robust and long-lasting antinociceptive effects (Molinari et al, 2013)
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