The Nociceptin Opioid Receptor (NOP) as a Therapeutic Target

[Chip (OP)]

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ListAttBBC  |  v6.12  |  2026-09-10  |  Andrew.human & Claude.ai

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Chip — August 24, 2026, 09:29:32 AM

source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001850/

The Nociceptin Opioid Receptor (NOP or Nociceptin receptor^Wiki) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

This is an area where therapy is available but without addiction and other nasty side effects like Tardive Dyskinesia. For MixChrissy since she brought this up.

Excerpts (and attached PDF for very technical, deep data (Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems):

Abstract

In the two decades since the discovery of the nociceptin opioid receptor (NOP) and its ligand, nociceptin/orphaninFQ (N/OFQ), steady progress has been achieved in understanding the pharmacology of this fourth opioid receptor/peptide system, aided by genetic and pharmacologic approaches. This research spawned an explosion of small-molecule NOP receptor ligands from discovery programs in major pharmaceutical companies. NOP agonists have been investigated for their efficacy in preclinical models of anxiety, cough, substance abuse, pain (spinal and peripheral) and urinary incontinence, whereas NOP antagonists have been investigated for treatment of pain, depression and motor symptoms in Parkinson’s disease. Translation of preclinical findings into the clinic is guided by PET and receptor occupancy studies, particularly for NOP antagonists. Recent progress in preclinical NOP research suggests that NOP agonists may have clinical utility for pain treatment and substance abuse pharmacotherapy. This review discusses the progress towards validating the NOP-N/OFQ system as a therapeutic target.

INTRODUCTION

The nociceptin opioid peptide receptor (NOP) was discovered in 1994, after cloning of the other three opioid receptors mu, delta and kappa (MOP, DOP and KOP in IUPHAR nomenclature).1-5 The characterization that rapidly followed clearly placed the NOP receptor (previously named the Opioid Receptor-like receptor-1, ORL-1) in the opioid receptor family of GPCRs, which couples to Gi/Go and inhibits adenylate cyclase activity. These properties informed the quest for an endogenous ligand for this ‘then orphan’ opioid receptor, and a year later, resulted in the successful identification, by two independent groups, of a heptadecapeptide from rat and porcine brains, which was named nociceptin and orphanin FQ, respectively.6,7 This neuropeptide, henceforth referred to as N/OFQ, has a high degree of similarity with the heptadecapeptide dynorphin, an endogenous neuropeptide that binds the kappa opioid receptor. It is therefore remarkable that N/OFQ has a 1000-fold lower affinity for the kappa opioid receptor than for NOP.8 Further, N/OFQ has no measurable affinity for the mu or delta opioid receptors. While both the NOP receptor and its endogenous ligand N/OFQ have structural and functional similarity to the other three opioid receptors and their endogenous ligands respectively, the NOP receptor does not bind classical opioid ligands, whereas the endogenous NOP ligand N/OFQ does not bind to the other opioid receptors, making the NOP–N/OFQ receptor-ligand system a class in itself, distinct from the opioid family in several important ways.

NOP Receptor-targeted Compounds in the Pipeline from Research to the Clinic

Fast forwarding to the present, the current state of progress in translation of NOP-N/OFQ research into clinical therapeutics development is, at the time of writing this review, limited to just one compound, a dual-targeted NOP agonist-MOP agonist Cebranopadol41 (1, GRT 6005, Table 1) from Grunenthal, for which Phase III clinical trials are currently ongoing, for treatment of various pain conditions.42, 43 Thus far, this is the most advanced into clinical development that any NOP-targeted compound has reached (Table 1). A NOP antagonist from Eli Lilly, 2 (LY2940094),44 is also in Phase II clinical trials for major depressive disorder45 and for alcohol dependence,46 but no further information is available regarding the outcome of these trials or future progress of this compound (Table 1). MK-5757 (3, Table 1), a NOP antagonist identified as a clinical candidate after extensive optimization by Banyu47, was in Phase II clinical trials, for the treatment of cognitive impairment in men with schizophrenia. Although the trial has been completed, no results have been yet disclosed.

Table 1

Status of NOP-targeted compounds that entered clinical development

Compound Name	Structure	NOP profile	Clinical Phase (Ref)	Indication
1 Cebranopadol	Open in a separate window	NOP full agonist-MOP full agonist	Ongoing Phase III42, 43	Various Pain modalities
2 LY2940094	Open in a separate window	NOP antagonist	Completed Phase II45, 46	Major Depressive Disorder Alcohol Dependence
3 MK-5757	Open in a separate window	NOP antagonist	Completed Phase II48	Cognitive Impairment in Schizophrenia
4 SCH486757	Open in a separate window	NOP full agonist	Completed Phase I (Discontinued)57	Cough
5 JNJ-19385899	Not available	NOP agonist	Completed Phase I (No information)51	Anxiety and Depression
6 Ser100, (ZP120)	Ac-RYYRWKKKKKKK-NH2	NOP partial agonist	Completed Phase IIa56	Treatment resistant systolic hypertension
7 JTC-801	Open in a separate window	NOP antagonist	Completed Phase II59	Neuropathic Pain Postoperative Pain
N/OFQ	FGGFTGARKSARKLANQ	Natural ligand NOP agonist	Completed Exploratory Phase II60	Neurogenic urinary incontinence

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