In vitro and in vivo pharmacological characterization of nociceptin/orphanin FQ tetrabranched derivatives. (September 2014)

• Record Type: Journal Article
• Authors: Rizzi, A; Malfacini, D; Cerlesi, M C; Ruzza, C; Marzola, E; Bird, M F; Rowbotham, D J; Salvadori, S; Guerrini, R; Lambert, D G; Calo, G
• Is Part Of: British journal of pharmacology. Volume 171:Number 17(2014:Sep.)
• Page Start: 4138
• Page End: 4153
• Publication Date: 2014-09
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12799
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12799-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>An innovative chemical approach, named peptide welding technology (PWT), allows the synthesis of multibranched peptides with extraordinary high yield, purity and reproducibility. With this approach, three different tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ) have been synthesized and named PWT1‐N/OFQ, PWT2‐N/OFQ and PWT3‐N/OFQ. In the present study we investigated the <italic>in vitro</italic> and <italic>in vivo</italic> pharmacological profile of PWT N/OFQ derivatives and compared their actions with those of the naturally occurring peptide.</p> </sec> <sec id="bph12799-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>The following <italic>in vitro</italic> assays were used: receptor and [<sup>35</sup>S]‐GTPγS binding, calcium mobilization in cells expressing the human N/OFQ peptide (NOP) receptor, or classical opioid receptors and chimeric G proteins, electrically stimulated mouse vas deferens bioassay. <italic>In vivo</italic> experiments were performed; locomotor activity was measured in normal mice and in animals with the NOP receptor gene knocked out [NOP(−/−)].</p> </sec> <sec id="bph12799-sec-0003" sec-type="section"> <title>Key Results</title> <p> <italic>In vitro</italic> PWT derivatives of N/OFQ behaved as high affinity potent and rather selective full agonists at human recombinant and animal native NOP receptors. <italic>In vivo</italic> PWT derivatives mimicked the inhibitory effects exerted by the natural peptide on locomotor activity showing 40‐fold higher potency and extremely longer lasting action. The effects of PWT2‐N/OFQ were no longer evident in NOP(−/−) mice.</p> </sec> <sec id="bph12799-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>The results showed that the PWT can be successfully applied to the peptide sequence of N/OFQ to generate tetrabranched derivatives characterized by a pharmacological profile similar to the native peptide and associated with a higher potency and marked prolongation of action <italic>in vivo</italic>.</p> </sec> </abstract>