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 (
USAN
280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk(于山國)was Ulleungdo(鬱陵島)
Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...
), 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
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 ...
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 Π...
(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; IC
50 = 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.
See also
* 6-Methylenedihydrodesoxymorphine
* Butorphanol
Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and ...
* Cyclorphan
Cyclorphan is an opioid analgesic of the morphinan family that was never marketed. It acts as a μ-opioid receptor (MOR) weak partial agonist or antagonist, κ-opioid receptor (KOR) full agonist, and, to a much lesser extent, δ-opioid receptor ...
* Ketorfanol
Ketorfanol (International Nonproprietary Name, INN, United States Adopted Name, USAN) (developmental code name SBW-22), or ketorphanol, is an opioid analgesic of the morphinan family that was found to possess "potent antinociception, antiwrithing ...
* Levallorphan
Levallorphan ( INN, BAN) (brand names Lorfan, Naloxifan, Naloxiphan), also known as levallorphan tartrate (USAN), is an opioid modulator of the morphinan family used as an opioid analgesic and opioid antagonist/antidote. It acts as an antagonist ...
* Levomethorphan
Levomethorphan (LVM) ( INN, BAN) is an opioid analgesic of the morphinan family that has never been marketed. It is the L-stereoisomer of racemethorphan (methorphan). The effects of the two isomers of the racemethorphan are quite different, with ...
* Levorphanol
Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain. It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan.
It was first described in Ge ...
* Nalmefene
Nalmefene is an opioid antagonist medication used in the management of opioid overdose and alcohol dependence. It is taken by mouth.
Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. ...
* Nalbuphine
Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.
Side effects of nalbuphine include sedation, sweatiness, clamm ...
* Nalorphine
Nalorphine () (brand names Lethidrone, Nalline), also known as ''N''-allylnormorphine, is a mixed opioid agonist–antagonist with opioid antagonist and analgesic properties. It was introduced in 1954 and was used as an antidote to reverse op ...
* Oxilorphan
* Proxorphan
Proxorphan ( INN), also known as proxorphan tartate ( USAN) (developmental code name BL-5572M), is an opioid analgesic and antitussive drug of the morphinan family that was never marketed. It acts preferentially as a κ-opioid receptor partial a ...
References
Analgesics
Convulsants
Delta-opioid receptor agonists
Dissociative drugs
Kappa-opioid receptor agonists
Morphinans
Phenols
Semisynthetic opioids
Cyclobutyl compounds
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