Norbuprenorphine is a major active metabolite of the opioid modulator buprenorphine. It is a μ-opioid, δ-opioid, and nociceptin receptor full agonist, and a κ-opioid receptor partial agonist. In rats, unlike buprenorphine, norbuprenorphine produces marked respiratory depression but with very little antinociceptive effect. In explanation of these properties, norbuprenorphine has been found to be a high affinity P-glycoprotein substrate, and in accordance, shows very limited blood-brain-barrier penetration.
ABT-239 is an H3-receptor inverse agonist developed by Abbott. It has stimulant and nootropic effects, and has been investigated as a treatment for ADHD, Alzheimer's disease, and schizophrenia. ABT-239 is more active at the human H3 receptor than comparable agents such as thioperamide, ciproxifan, and cipralisant. It was ultimately dropped from human trials after showing the dangerous cardiac side effect of QT prolongation, but is still widely used in animal research into H3 antagonists / inverse agonists.
The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
Neuropeptide Y receptor type 5 is a protein that in humans is encoded by the NPY5R gene.
JTC-801 is an opioid analgesic drug used in scientific research.
NESS-0327 is a drug used in scientific research which acts as an extremely potent and selective antagonist of the cannabinoid receptor CB1. It is much more potent an antagonist, and more selective for the CB1 receptor over CB2, than the more commonly used ligand rimonabant, with a Ki at CB1 of 350fM (i.e. 0.00035nM) and a selectivity of over 60,000x for CB1 over CB2. Independently, two other groups have described only modest nanomolar CB1 affinity for this compound (125nM and 18.4nM). Also unlike rimonabant, NESS-0327 does not appear to act as an inverse agonist at higher doses, instead being a purely neutral antagonist which blocks the CB1 receptor but does not produce any physiological effect of its own.
NNC 63-0532 is a nociceptoid drug used in scientific research. It acts as a potent and selective agonist for the nociceptin receptor, also known as the ORL-1 receptor.
Perzinfotel (EAA-090) is a drug which acts as a potent NMDA antagonist. It has neuroprotective effects and has been investigated for the treatment of stroke, but lacks analgesic effects. Nevertheless, it shows a good safety profile compared to older drugs, although further development of this drug has been discontinued.
J-113,397 is an opioid drug which was the first compound found to be a highly selective antagonist for the nociceptin receptor, also known as the ORL-1 receptor. It is several hundred times selective for the ORL-1 receptor over other opioid receptors, and its effects in animals include preventing the development of tolerance to morphine, the prevention of hyperalgesia induced by intracerebroventricular administration of nociceptin, as well as the stimulation of dopamine release in the striatum, which increases the rewarding effects of cocaine, but may have clinical application in the treatment of Parkinson's disease.
Ro64-6198 is a nociceptoid drug used in scientific research. It acts as a potent and selective agonist for the nociceptin receptor, also known as the ORL-1 receptor, with over 100x selectivity over other opioid receptors. It produces anxiolytic effects in animal studies equivalent to those of benzodiazepine drugs, but has no anticonvulsant effects and does not produce any overt effects on behaviour. However it does impair short-term memory, and counteracts stress-induced anorexia. It also has antitussive effects, and reduces the rewarding and analgesic effects of morphine, although it did not prevent the development of dependence. It has been shown to reduce alcohol self-administration in animals and suppressed relapses in animal models of alcoholism, and ORL-1 agonists may have application in the treatment of alcoholism.
Lu AA-33810 is a drug developed by Lundbeck, which acts as a potent and highly selective antagonist for the Neuropeptide Y receptor Y5, with a Ki of 1.5nM and around 3300x selectivity over the related Y1, Y2 and Y4 receptors. In animal studies it produced anorectic, antidepressant and anxiolytic effects, and further research is now being conducted into its possible medical application in the treatment of eating disorders.
PD-128,907 is a drug used in scientific research which acts as a potent and selective agonist for the dopamine D2 and D3 receptors. It is used for studying the role of these receptors in the brain, in roles such as inhibitory autoreceptors that act to limit further dopamine release, as well as release of other neurotransmitters. In animal studies it has been shown to reduce toxicity from cocaine overdose.
The alpha-3 beta-4 nicotinic receptor, also known as the α3β4 receptor and the ganglion-type nicotinic receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β4 subunits. It is located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or presynaptic excitation, mainly by increased Na+ and K+ permeability.
O-1269 is a drug that is a diarylpyrazole derivative, related to potent cannabinoid antagonist drugs such as rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full or partial agonists at the cannabinoid receptors rather than antagonists, and so produce the usual effects expected of cannabinoid agonists in animal tests, such as sedation and analgesic effects. The N-heptyl homolog O-1270 and the N-propyl homolog O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker binding affinity at cannabinoid receptors compared to the pentyl homolog O-1269. Agonist-like and atypical cannabinoid activity has also been observed with a number of related compounds.
Cebranopadol is an opioid analgesic of the benzenoid class which is currently under development internationally by Grünenthal, a German pharmaceutical company, and its partner Depomed, a pharmaceutical company in the United States, for the treatment of a variety of different acute and chronic pain states. As of November 2014, it is in phase III clinical trials.
Thienorphine is a very potent, extremely long-acting, orally-active opioid analgesic with mixed agonist–antagonist properties which was developed by the Beijing Institute of Pharmacology and Toxicology as a potential treatment for opioid dependence. It is a high-affinity, balanced ligand of the μ-, δ-, and κ-opioid receptors, behaving as a partial agonist of the μ- and κ-opioid receptors and as an antagonist of the δ-opioid receptor. It also possesses relatively low affinity for the nociceptin receptor, where it acts as an antagonist.
Burapitant (SSR-240,600) is a drug developed by Sanofi-Aventis which was one of the first compounds developed that acts as a potent and selective antagonist for the NK1 receptor. While burapitant itself did not proceed beyond early clinical trials and was never developed for clinical use in humans, promising animal results from this and related compounds have led to a number of novel drugs from this class that have now been introduced into medical use.
SR-16435 is a drug which acts as a potent partial agonist at both the μ-opioid receptor and nociceptin receptor. In animal studies it was found to be a potent analgesic, with results suggestive of reduced development of tolerance and increased activity against neuropathic pain compared to classic μ-selective agonists.
BU08028 is a drug which acts as a potent partial agonist at both the μ-opioid receptor and nociceptin receptor. It is a homologue of buprenorphine extended by just one carbon on the side chain, but has relatively greater activity at the nociceptin receptor, which is thought to reduce the abuse potential without compromising analgesia.
AC-90179 is a piperidine derivative which acts as an inverse agonist at the 5-HT2A serotonin receptor and an antagonist at 5-HT2C. It was developed as a potential antipsychotic but was not pursued for medical applications due to poor oral bioavailability, however it continues to be used as a tool compound in pharmacological research.
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