Oripavine 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 ...
and the major metabolite of
thebaine
Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...
. It is the parent compound from which a
series
Series may refer to:
People with the name
* Caroline Series (born 1951), English mathematician, daughter of George Series
* George Series (1920–1995), English physicist
Arts, entertainment, and media
Music
* Series, the ordered sets used in ...
of semi-synthetic
opioids are derived, which includes the compounds
etorphine and
buprenorphine
Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal ...
. Although its
analgesic potency is comparable to
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 ...
, it is not used clinically due to its severe
toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
and low
therapeutic index
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
. Due to its use in manufacture of strong opioids, oripavine is a controlled substance in some jurisdictions.
Pharmacological properties
Oripavine possesses an
analgesic potency comparable to morphine; however, it is not clinically useful due to severe
toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
and low
therapeutic index
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
. In both
mice and
rats, toxic doses caused
tonic-clonic seizures followed by death, similar to
thebaine
Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...
.
Oripavine has a potential for
dependence which is significantly greater than that of
thebaine
Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...
but slightly less than that of
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 ...
.
Bridged derivatives
Of much greater relevance are the properties of the orvinols, a large family of semi-synthetic oripavine derivatives classically synthesized by the
Diels-Alder reaction of
thebaine
Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...
with an appropriate dienophile followed by 3-''O''-demethylation to the corresponding bridged oripavine. These compounds were developed by the group led by
K. W. Bentley in the 1960s, and these
Bentley compounds
The Bentley compounds are a class of semi-synthetic opioids that were first synthesized by K. W. Bentley by Diels-Alder reaction of thebaine with various dienophiles. The compounds are also known as thevinols, orvinols, or bridged oripavine der ...
represent the first series of "super-potent"
μ-opioid agonists, with some compounds in the series being over 10,000 times the potency of morphine as an analgesic. The simple bridged oripavine parent compound
6,14-endoethenotetrahydrooripavine is already 40 times the potency of morphine, but adding a branched tertiary alcohol substituent on the C7 position results in a wide range of highly potent compounds.
![Bridged_oripavine_general](https://upload.wikimedia.org/wikipedia/commons/0/08/Bridged_oripavine_general.svg)
Other notable derivatives then result from further modification of this template, with saturation of the 7,8-double bond of etorphine resulting in the even more potent
dihydroetorphine (up to 12,000× potency of morphine) and acetylation of the 3-hydroxy group of etorphine resulting in
acetorphine
Acetorphine is a potent opioid analgesic, up to 8700 times stronger than morphine by weight. It is a derivative of the more well-known opioid etorphine, which is used as a very potent veterinary painkiller and anesthetic medication, primarily f ...
(8700× morphine)—although while the isopentyl homologue of etorphine is nearly three times more potent, its 7,8-dihydro and 3-acetyl derivatives are less potent than the corresponding derivatives of etorphine at 11,000 and 1300 times morphine, respectively. Replacing the ''N''-methyl group with cyclopropylmethyl results in
opioid antagonist
An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.
Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the ...
s such as
diprenorphine
Diprenorphine (brand name Revivon; former developmental code name M5050), also known as diprenorfin, is a non-selective, high- affinity, weak partial agonist of the μ- (MOR), κ- (KOR), and δ-opioid receptor (DOR) (with equal affinity) which ...
(M5050, which is used as an antidote to reverse the effects of etorphine, M99), and
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 ...
s such as
buprenorphine
Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal ...
, which is widely used in the treatment of
opioid addiction
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Op ...
.
Legal status
Due to the relative ease of synthetic modification of oripavine to produce other
narcotics (by either direct or indirect routes via
thebaine
Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...
), the
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
's Expert Committee on Drug Dependence recommended in 2003 that oripavine be controlled under Schedule I of the 1961
Single Convention on Narcotic Drugs
The Single Convention on Narcotic Drugs, 1961 (Single Convention, 1961 Convention, or C61) is an international treaty that controls activities (cultivation, production, supply, trade, transport) of specific narcotic drugs and lays down a syste ...
. On March 14, 2007, the
United Nations
The United Nations (UN) is an intergovernmental organization whose stated purposes are to maintain international peace and security, develop friendly relations among nations, achieve international cooperation, and be a centre for harmoniz ...
Commission on Narcotic Drugs
The Commission on Narcotic Drugs (CND) is one of the functional commissions of the United Nations' Economic and Social Council (ECOSOC), and is the central drug policy-making body within the United Nations System. The CND also has important man ...
formally decided to accept these recommendations, and placed oripavine in the Schedule I.
Until recently, oripavine was a
Schedule II drug in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
by default as a
thebaine
Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...
derivative, although it was not explicitly listed. However, as a member state under the 1961
Single Convention on Narcotic Drugs
The Single Convention on Narcotic Drugs, 1961 (Single Convention, 1961 Convention, or C61) is an international treaty that controls activities (cultivation, production, supply, trade, transport) of specific narcotic drugs and lays down a syste ...
, the US was obliged to specifically control the substance under the
Controlled Substances Act following its international control by the UN Commission on Narcotic Drugs. On September 24, 2007, the
Drug Enforcement Administration
The Drug Enforcement Administration (DEA; ) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating drug trafficking and distribution within the U.S. It is the lead agency for domestic en ...
formally added oripavine to Schedule II.
Under the Controlled Substances Act 1970, oripavine has an ACSCN of 9330 and a 2013 manufacturing quota of .
Biosynthesis
This molecule is biosynthetically related to the morphinane derivatives metabolism, where
thebaine
Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar ...
and
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 ...
are implicated.
References
{{Opioidergics
4,5-Epoxymorphinans
Glycine receptor antagonists
Opiates
Oripavines
Phenol ethers
Poisons