source:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001850/The Nociceptin Opioid Receptor (NOP or Nociceptin receptorWiki) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical UtilityThis 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):
AbstractIn 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.
INTRODUCTIONThe 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 ClinicFast 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 |
| NOP full agonist-MOP full
agonist | Ongoing Phase III42, 43 | Various Pain modalities |
2 LY2940094 |
| NOP antagonist | Completed Phase II45, 46 | Major
Depressive Disorder Alcohol Dependence |
3 MK-5757 |
| NOP antagonist | Completed Phase II48 | Cognitive Impairment
in Schizophrenia |
4 SCH486757 |
| 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 |
| 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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