Nociceptin/orphanin FQ (N/OFQ) modulates various biological functions, including nociception, via selective stimulation of the N/OFQ peptide receptor (NOP). UFP-101 is a novel NOP ligand designed to bind [Nphe1] chemically in the same molecule, eliminating potency and the [Arg14, Lys15] substitution increases ligand potency and duration of action in vivo. UFP-101 is a useful pharmacological tool for studying the central and peripheral biological functions of NOFQ-NOP receptor system regulation and for determining the therapeutic potential of NOP receptor ligands.
UFP-101 has high affinity (pKi 10.2) and selectivity (reduced 3000 times higher than classical opioid receptors) with recombinant NOP receptors expressed by CHO cells. In functional studies, such as stimulation of GTPγ[35S] binding and inhibition of forskolin to stimulate cAMP accumulation in CHOhNOP cells, UFP-101 competitively antagonized NOFQ effects being inactive per se. In the GTPγ[35S] binding assay, UFP-101 antagonistic properties were also confirmed against a panel of NOP agonists including the peptides NOFQ (1–13) NH2, [(pF)Phe4]NOFQ(1–13)-NH2 and [Arg14, Lys15]N/OFQ, and the non-peptide Ro 64-6198. In the same CHOhNOP preparation, UFP-101 also prevented NOFQ-induced NOP binding site internalization and was inactive when tested alone. The antagonist potency of UFP-101 is approximately ten fold higher than that of the NOP antagonist [Nphe1]NOFQ(1–13)-NH2. This difference in potency is similar to that of the agonists NOFQ and [Arg14, Lys15]NOFQ.
UFP-101 completely blocks the N/OFQ effect, but is not the endogenous agonist dose ratio induced by endomorphin-1, ie. 10/1, similar to several groups used to counteract N/OFQ, including supraspinal pronociceptive effects, inhibiting exercise activity and rotating rod performance, anti-anxiety-like effects, stimulating food intake, bradycardia and hypotension, diuresis, inhibition of intestinal movement and secretion function. Thus, the result demonstrates the selectivity of UFP-101 and its in vivo antagonist potency, and together with those in the literature demonstrates the usefulness of this NOP ligand in vivo pharmacology and pathophysiological studies.
Becker J A, Wallace A, Garzon A, et al. Ligands for kappa-opioid and ORL1 receptors identified from a conformationally constrained peptide combinatorial library. J Biol Chem, 1999, 274, 27513–27522.
Bigoni R, Calo G, Rizzi A, et al. In vitro characterization of J-113397, a non-peptide nociceptinorphanin FQ receptor antagonist. Naunyn Schmiedeberg's Arch Pharmacol, 2000, 361, 565–568.
Calo G, Rizzi A, Rizzi D, et al. [Nphe(1), Arg(14), Lys(15)]nociceptin-NH(2), a novel potent and selective antagonist of the nociceptinorphanin FQ receptor. Br J Pharmacol, 2002, 136, 303–311.