Xorphanol (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) (developmental code name TR-5379 or TR-5379M), also known as xorphanol mesylate (

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), is an

opioid 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 ...

analgesic of the

morphinan Morphinan is the prototype chemical structure of a large chemical class of psychoactive drugs, consisting of opiate analgesics, cough suppressants, and dissociative hallucinogens, among others. Structure Morphinan has a phenanthrene core struct ...

family that was never marketed. Xorphanol is a mixed agonist–antagonist of

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin ...

s, acting preferentially as a high- efficacy

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

/near-

full agonist 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 a ...

of the

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, 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 op ...

(K_i = 0.4 nM; EC₅₀ = 3.3 nM; = 49%; = 0.84) and to a lesser extent as a

of the

μ-opioid receptor 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 � ...

(K_i = 0.25 nM; IC₅₀ = 3.4 nM; = 29%) with lower relative

intrinsic activity Intrinsic activity (IA) and efficacy refer to the relative ability of a drug- receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its mol ...

and marked antagonistic potential (including the ability to antagonize

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

-induced effects and induce

opioid withdrawal Opioid withdrawal is a set of symptoms (a syndrome) arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, ...

in opioid-dependent individuals). The drug has also been found to act as an agonist of the

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous lig ...

(K_i = 1.0 nM; IC₅₀ = 8 nM; = 76%). Xorphanol produces potent analgesia, and was originally claimed to possess a minimal potential for dependence or abuse. Moreover,

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s in

animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including geography, art history, ant ...

were relatively mild, with only sedation and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

being prominent, although it also produced

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

at the highest dose tested. However, human trials revealed additional side effects such as headaches and euphoria, and this was the subject of a lawsuit between the drug's inventors and the company to which they had licensed the marketing rights, which claimed that these side effects had not been revealed to them during the license negotiations.''Maruho Company Ltd v Miles Inc'' (1993) 13 F.3d 6
/ref> As a result of this dispute, the drug was never marketed commercially.

References

Analgesics Convulsants Delta-opioid receptor agonists Dissociative drugs Kappa-opioid receptor agonists Morphinans Phenols Semisynthetic opioids Cyclobutyl compounds {{analgesic-stub

See also

References