Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: Research tools and potential therapeutic agents

Abstract

The 17-amino acid neuropeptide nociceptin/Orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioid receptor-like (ORL1) receptor, a fourth member of the classical μ, δ, and κ opioid receptor family. Although ORL1 clearly belongs to the opioid receptor family, it does not bind classical opiates and the ORL1-N/OFQ system has pharmacological actions distinct from the opioid receptor system. This new ligand-receptor system has generated active interest in the opioid community because of its wide distribution and involvement in a myriad of neurological pathways. The past two years have witnessed tremendous advances in the design and discovery of very potent and selective peptide and nonpeptide agonist and antagonist ligands at ORL1. These discoveries have facilitated the understanding of the role of the ORL1-N/OFQ system in a variety of processes such as pain modulation, anxiety, food intake, learning, memory, neurotransmitter release, reward pathways, and tolerance development. The ORL1 receptor therefore represents a new molecular target for the design of novel agents for anxiety, analgesia, and drug addiction. Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics. This review presents an overview of the various peptide and nonpeptide ORL1 ligands with an emphasis on their potential therapeutic utility in various human disorders.

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

“…the agonist Ro 64-6198 [29] and the antagonists J-113397 [46] and SB-612111 [52]; ii) small peptides such as the hexapeptides Ac-RYYRWK-NH 2 and Ac-RYYRIK-NH 2 [19] and the pseudopentadapeptide III-BTD [2]; iii) a large series of N/ OFQ related peptides chemically modified for increasing agonist potency or for reducing or eliminating efficacy. Details about these three classes of NOP ligands can be found in recent review articles such as [53] and [3]. Our research group has substantially contributed to the identification of N/OFQ related NOP ligands by performing a series of structure activity studies which allow the identification of the following useful chemical modifications: C-terminus amidation that increases agonist potency and reduces susceptibility to peptidases [23], reduction of the first peptide bond of N/OFQ which reduces ligand efficacy [8], shift of the Phe 1 side chain to the nitrogen atom that eliminates efficacy [25], and substitutions on the Phe 4 side chain (e.g.…”

Blockade of Nociceptin/Orphanin FQ Receptor Signaling in Rat Substantia Nigra Pars Reticulata Stimulates Nigrostriatal Dopaminergic Transmission and Motor Behavior

“…N/OFQ and its receptor are diffusely expressed in the brain, and evidence for heterogeneity of N/OFQ sites, possibly representing splice variants or posttranslational modifications of the NOP receptor, has been presented Mogil and Pasternak, 2001). The pharmacology of the N/OFQ-NOP receptor system has been extensively characterized by means of selective NOP receptor ligands (Zaveri, 2003). Conversely, less is known on the physiology of endogenous N/OFQ, possibly because of the lack of potent and selective antagonists, which only recently have been developed: the peptide UFP-101 ([Nphe 1 ,Arg 14 ,Lys 15 ]N/OFQ(1-13)-NH 2 ) ) and the nonpeptide J-113397 (1-[3R,4 R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one) (Kawamoto et al, 1999;Ozaki et al, 2000).…”

Synthesis and Evaluation as NOP Ligands of Some Spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones and Spiro[piperidine-4,5'(6'H)-[1,2,4]triazolo[1,5-c]quinazolines]

“…12) At the same time, consistent advances have been attained in the design and discovery of new ligands, and many nonpeptide small molecules were developed as agonists or antagonists. [13][14][15][16][17] Among several scaffolds, spiropiperidines showed to be an interesting and promising class of NOP ligands. They are structurally related to lofentanyl (Fig.…”