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| Formula | C21H13ClF6N2O5S |
| Molar mass | 554.84 g·mol−1 |
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RQ-00203078 is a drug which acts as a potent and selective blocker of the TRPM8 ion channel, which is the main receptor responsible for the sensation of cold. It was developed as a potential analgesic, and blocks the development of hyperalgesia following exposure to cold temperatures or chronic morphine administration. [1] [2] [3]
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, and suppressing cough. Extremely potent opioids such as carfentanil are approved only for veterinary use. Opioids are also frequently used non-medically for their euphoric effects or to prevent withdrawal. Opioids can cause death and have been used for executions in the United States.
Hyperalgesia is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can cause hypersensitivity to stimulus. Prostaglandins E and F are largely responsible for sensitizing the nociceptors. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.
18-Methoxycoronaridine, also known as zolunicant, is a derivative of ibogaine invented in 1996 by the research team around the pharmacologist Stanley D. Glick from the Albany Medical College and the chemists Upul K. Bandarage and Martin E. Kuehne from the University of Vermont. In animal studies it has proved to be effective at reducing self-administration of morphine, cocaine, methamphetamine, nicotine and sucrose. It has also been shown to produce anorectic effects in obese rats, most likely due to the same actions on the reward system which underlie its anti-addictive effects against drug addiction.
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.
Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is an uncommon condition of generalized pain caused by the long-term use of high dosages of opioids such as morphine, oxycodone, and methadone. OIH is not necessarily confined to the original affected site. This means that if the person was originally taking opioids due to lower back pain, when OIH appears, the person may experience pain in the entire body, instead of just in the lower back. Over time, individuals taking opioids can also develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). This means that if the person originally felt pain from twisting or from sitting too long, the person might now additionally experience pain from a light touch or from raindrops falling on the skin.
The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.
Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.
Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.
Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.
WAY-100635 is a piperazine drug and research chemical widely used in scientific studies. It was originally believed to act as a selective 5-HT1A receptor antagonist, but subsequent research showed that it also acts as potent full agonist at the D4 receptor. It is sometimes referred to as a silent antagonist at the former receptor. It is closely related to WAY-100135.
Tezampanel is a drug originally developed by Eli Lilly which acts as a competitive antagonist of the AMPA and kainate subtypes of the ionotropic glutamate receptor family, with selectivity for the GluR5 subtype of the kainate receptor. It has neuroprotective and anticonvulsant properties, the former of which may, at least in part, occur via blockade of calcium uptake into neurons.
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.
2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a research drug which was one of the first compounds found to act as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. After being originally patented as a liquid crystal for LCDs, it was developed by the pharmaceutical company Novartis in the late 1990s. It was found to produce neuroprotective effects following acute brain injury in animal studies, although it was unclear whether these results were purely from mGluR5 blockade as it also acts as a weak NMDA antagonist, and as a positive allosteric modulator of another subtype mGlu4, and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons. It was also shown to produce antidepressant and anxiolytic effects in animals, and to reduce the effects of morphine withdrawal, most likely due to direct interaction between mGluR5 and the μ-opioid receptor.
3-( ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP, MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.
(+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (-)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.
AZD-1940 is a drug developed by AstraZeneca, that is a peripherally selective cannabinoid agonist which binds with high affinity to both the CB1 and CB2 receptors. It was developed for the treatment of neuropathic pain, but while it showed good peripheral selectivity in animal studies, in human clinical trials it failed to show sufficient analgesic efficacy and produced unexpectedly strong side effects associated with central cannabinoid activity, and so was discontinued from further development.
WS-12 is a chemical compound that acts as a potent and selective activator of the TRPM8 calcium channel, which is responsible for the sensation of coldness produced by menthol. It is slightly less potent as a TRPM8 activator compared to icilin, but is much more selective for TRPM8 over related calcium channels. It produces analgesic and antiinflammatory effects in animal models with similar efficacy to menthol and a reduced side effect profile.
PF-05105679 is a drug which acts as a potent and selective blocker of the TRPM8 ion channel, which is the main receptor responsible for the sensation of cold. It was developed as a potential analgesic, and blocks the sensation of cold in both animals and human trials. It also lowers core body temperature in small mammals, but does not produce this effect in humans in the normal dosage range.
AMG-333 is a drug which acts as a potent and selective blocker of the TRPM8 ion channel, which is the main receptor responsible for the sensation of cold. It was developed as a potential treatment for migraine.
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