Biased Agonism at Nociceptin/Orphanin FQ Receptors: A Structure Activity Study on N/OFQ(1–13)-NH₂

Abstract

Nociceptin/orphanin FQ (N/OFQ) controls different biological functions via selective stimulation of the N/OFQ peptide (NOP) receptor. The pleiotropic actions of N/OFQ may limit the development of NOP ligands as innovative drugs in different therapeutic areas. The pharmacological concept of functional selectivity (aka biased agonism) might be useful for amplifying beneficial actions and/or counteracting side effects. Thus, molecules with large bias factors toward G protein or β arrestin are required for investigating the translational value of NOP biased modulation. Herein, the biased behavior of a heterogeneous library of NOP-targeting peptide derivatives was evaluated in vitro with the aim to provide possible insights into the structural determinants that govern the selective activation of G protein versus β-arrestin. Our results demonstrate that lipidation of N/OFQ(1−13)-NH 2 is a useful strategy for obtaining G protein biased agonists for the NOP receptor.

Pharmacology of Kappa Opioid Receptors: Novel Assays and Ligands

“…The homo tetrameric PWT2-Dyn A was obtained grafting four molecules of [Cys 18 ]Dyn A with the PWT2 core in a classical thiol-Michael reaction using experimental conditions previously optimized for the synthesis of nociceptin/orphanin FQ tetra branched derivatives ( Guerrini et al, 2014 ). Similarly, the Dyn A analogue, Dyn A-palmitic was synthesized reacting in solution [Cys 18 ]Dyn A with a palmitoyl functionalized maleimide moiety ( Pacifico et al, 2020 ).…”

An Italian Expert Consensus on the Use of Opioids for the Management of Chronic Non-Oncological Pain in Clinical Practice: Focus on Buprenorphine.

“…These "biased" profile is due to the reduced capability of the drug in recruiting downstream signaling β-arrestin 2. 43 An important difference is that oliceridine shows a similar withdrawal syndrome when injected with the naloxone, confirming the hypothesis that the β-arrestin 2 pathway is critical in tolerance but not in the addiction, 44,45 while buprenorphine is characterized by a lower risk of abuse and, more importantly, it has been properly used in detoxification protocols of opioid abuse. 46 Buprenorphine treatment, by blocking the central sensitization mechanism involved in hyperalgesia and allodynia: a. is useful for refractory neuropathic and nociceptive pain; b.…”

Membrane protein production and formulation for drug discovery

“…This type of assay was originally applied to discover biased ligands that favor G-protein signaling for opioid receptors [61], ultimately resulting in the first drug designed as a biased agonist, oliceridine (FDA-approved in August 2020), which has reduced adverse effects compared with morphine. Similar assays have facilitated the discovery of biased ligands for the nociception opioid peptide (NOP) [62] and serotonin HT1A [63] receptors. Although ion channel/transporter interactions with function-modulating proteins are not as well characterized compared with GPCRs, there is great potential to apply similar assays to those systems, as in a recent example where a peptide disrupting the Na v 1.6/fibroblast growth factor interaction was discovered [64].…”