An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.
An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.
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.
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.
TRIMU-5 is a selective agonist of the μ2-opioid receptor and antagonist of the μ1-opioid receptor. It produces analgesia in animals that differs from that of conventional μ-opioid receptor agonists but that can still be blocked by μ-opioid receptor antagonists. TRIMU-5 can also block the analgesic effects of μ-opioid receptor agonists like morphine. In addition to analgesia, TRIMU-5 inhibits gastrointestinal transit, a known effect of μ2-opioid receptor activation.
Propiram is a partial μ-opioid receptor agonist and weak μ antagonist analgesic from the ampromide family of drugs related to other drugs such as phenampromide and diampromide. It was invented in 1963 in the United Kingdom by Bayer but was not widely marketed, although it saw some limited clinical use, especially in dentistry. Propiram reached Phase III clinical trials in the United States and Canada.
In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist while under other conditions, behaves as an antagonist.
U-50488 is a drug which acts as a highly selective κ-opioid agonist, but without any μ-opioid antagonist effects. It has analgesic, diuretic and antitussive effects, and reverses the memory impairment produced by anticholinergic drugs. U-50488 was one of the first selective kappa agonists invented and research on its derivatives has led to the development of a large family of related compounds. This compound has never received FDA approval and there are no reported human cases in the literature involving an U-50488 overdose.
Alazocine, also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and opioid antagonist. Moreover, one of its enantiomers was the first compound that was found to selectively label the σ1 receptor, and led to the discovery and characterization of the receptor.
Bromadoline (U-47931E) is an opioid analgesic selective for the μ-opioid receptor developed by the Upjohn company in the 1970s. The drug has a potency lying between that of codeine and morphine, being slightly stronger than pentazocine. Bromadoline is related to AH-7921 and U-47700.
R-30490 is an opioid analgesic related to the highly potent animal tranquilizer carfentanil, and with only slightly lower potency. It was first synthesised by a team of chemists at Janssen Pharmaceutica led by Paul Janssen, who were investigating the structure-activity relationships of the fentanyl family of drugs. R-30490 was found to be the most selective agonist for the μ-opioid receptor out of all the fentanyl analogues tested, but it has never been introduced for medical use in humans, although the closely related drug sufentanil is widely used for analgesia and anesthesia during major surgery.
U-47700, also known as U4, pink heroin, pinky, and pink, is an opioid analgesic drug developed by a team at Upjohn in the 1970s which has around 7.5 times the potency of morphine in animal models.
Bucinnazine is an opioid analgesic drug that was widely used in China to treat pain in cancer patients as of 1986. It is one of the most potent compounds among a series of piperazine-amides first synthesized and reported in Japan in the 1970s. Bucinnazine has analgesic potency comparable to that of morphine, but with a relatively higher therapeutic index.
Metonitazene is an analgesic compound related to etonitazene, which was first reported in 1957, and has been shown to have approximately 1000 times the potency of morphine by central routes of administration, but if used orally it has been shown to have approximately 10 times the potency of morphine.
Metodesnitazene is a benzimidazole derivative with opioid effects, though unlike related compounds such as metonitazene and etodesnitazene which are quite potent, metodesnitazene is only around the same potency as morphine in animal studies. It is illegal in both the US and UK.
N-Desethylisotonitazene (norisotonitazene) is a benzimidazole opioid with potent analgesic effects which has been sold as a designer drug. It was first identified in 2023 as an active metabolite of the closely related compound isotonitazene, and was found to have similar potency. It is one of the strongest benzimidazole opioids discovered, with an analgesic strength 20 times stronger than fentanyl.
3,4-MDO-U-47700 is an opioid analgesic which has been sold as a designer drug, first appearing in 2017 after U-47700 itself was banned in various jurisdictions. It is less potent than U-47700 but is still a full agonist at the μ-opioid receptor, with slightly higher potency than morphine. It is illegal in Virginia.
U-48800 is an opioid analgesic which has been sold as a designer drug. Unlike U-47700, it is primarily active as a kappa opioid receptor agonist with only moderate affinity at the mu opioid receptor. Nevertheless, it has still appeared on the recreational drug market, often as a component of combinations with other drugs, and has been linked to numerous drug overdose cases.
Methocinnamox (MCAM) is an opioid receptor antagonist. It is a pseudo-irreversible non-competitive antagonist of the μ-opioid receptor and a competitive antagonist of the κ- and δ-opioid receptors. The drug has a very long duration of action of up to months with a single dose due to its pseudo-irreversibility. It is administered in animals by intravenous or subcutaneous injection.
