Oripavine
Encyclopedia
Oripavine is an opiate
and the major metabolite of thebaine
. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine
and buprenorphine
. Although its analgesic
potency is comparable to morphine
, it is not used clinically due to its severe toxicity
and low therapeutic index
.
potency comparable to morphine; however, it is not clinically useful due to severe toxicity
and low therapeutic index
. In both mice
and rats
, toxic doses caused tonic-clonic seizure
s followed by death, similar to thebaine
. Oripavine has a potential for dependence
which is significantly greater than that of thebaine
but slightly less than that of morphine
.
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
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 40x the potency of morphine, but adding a branched tertiary alcohol substituent on the C7 position results in a wide range of highly potent compounds.
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 12,000x potency of morphine) and acetylation of the 3-hydroxy group of etorphine resulting in acetorphine
(8700x 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 11000x and 1300x morphine respectively. Replacing the N-methyl group with cyclopropylmethyl results in opioid antagonist
s such as diprenorphine
(which is used as an antidote to reverse the effects of etorphine), and partial agonist
s such as buprenorphine
, which is widely used in the treatment of opioid addiction.
), the World Health Organization
's Expert Committee on Drug Dependence recommended in 2003 that oripavine be controlled under Schedule I of the 1961 Single Convention on Narcotic Drugs
. On March 14, 2007, the United Nations
Commission on Narcotic Drugs
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
by default as a thebaine
derivative, although it was not explicitly listed. However, as a member state under the 1961 Single Convention on Narcotic Drugs
, 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
formally added oripavine to Schedule II.
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
and the major metabolite of thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...
. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine
Etorphine
Etorphine is a semi-synthetic opioid possessing an analgesic potency approximately 200 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in related plants, Papaver orientale and Papaver...
and buprenorphine
Buprenorphine
Buprenorphine is a semi-synthetic opioid that is used...
. Although its analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
potency is comparable to morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, it is not used clinically due to its severe toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
and low therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
.
Pharmacological properties
Oripavine possesses an analgesicAnalgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
potency comparable to morphine; however, it is not clinically useful due to severe toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
and low therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
. In both mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
and rats
RATS
RATS may refer to:* RATS , Regression Analysis of Time Series, a statistical package* Rough Auditing Tool for Security, a computer program...
, toxic doses caused tonic-clonic seizure
Tonic-clonic seizure
Tonic–clonic seizures are a type of generalized seizure that affects the entire brain...
s followed by death, similar to thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...
. Oripavine has a potential for dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
which is significantly greater than that of thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...
but slightly less than that of morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
.
Bridged Oripavine derivatives
Of much greater relevance are the properties of the orvinols, a large family of semi-synthetic oripavine derivatives classically synthesised by the Diels-Alder reaction of thebaineThebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...
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
Bentley compounds
Bentley compounds are a class of semi-synthetic opioids that were first synthesized from thebaine by K. W. Bentley. The compounds include: oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine. They represent the first series of more potent μ-opioid agonists, with...
represent the first series of "super-potent" μ-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
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 40x the potency of morphine, but adding a branched tertiary alcohol substituent on the C7 position results in a wide range of highly potent compounds.
| Drug name | R | Analgesic Potency (Morphine = 1) |
|---|---|---|
| methyl | 63 | |
| ethyl | 330 | |
| Etorphine Etorphine Etorphine is a semi-synthetic opioid possessing an analgesic potency approximately 200 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in related plants, Papaver orientale and Papaver... |
n-propyl | 3200 |
| n-butyl | 5200 | |
| isobutyl | 10 | |
| n-pentyl | 4500 | |
| isopentyl | 9200 | |
| n-hexyl | 58 | |
| O-desmethyl-7-PET 7-PET 7-PET was discovered by K.W. Bentley and is a potent analgesic drug, 300 times the potency of morphine by weight. It is related to the more well-known oripavine derivative opioid etorphine, which is used as a very potent veterinary painkiller and anesthetic medication, used primarily for the... |
phenethyl | 2200 |
| phenyl | 34 | |
| cyclopentyl | 70 | |
| cyclohexyl | 3400 | |
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
Dihydroetorphine
Dihydroetorphine was developed by K.W.Bentley at McFarlan-Smith in the 1960s and is a potent analgesic drug , which is used mainly in China...
(up to 12,000x potency of morphine) and acetylation of the 3-hydroxy group of etorphine resulting in acetorphine
Acetorphine
Acetorphine is a potent analgesic drug, 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 for the sedation of large animals such as elephants,...
(8700x 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 11000x and 1300x morphine respectively. Replacing the N-methyl group with cyclopropylmethyl results in opioid antagonist
Opioid antagonist
An opioid antagonist is a receptor antagonist that acts on opioid receptors.Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the opioid receptors with higher affinity than agonists but do not activate the receptors...
s such as diprenorphine
Diprenorphine
Diprenorphine is an opioid antagonist used to reverse the effects of the super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals in veterinary medicine....
(which is used as an antidote to reverse the effects of etorphine), and partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
s such as buprenorphine
Buprenorphine
Buprenorphine is a semi-synthetic opioid that is used...
, which is widely used in the treatment of opioid addiction.
Legal status
Due to the relative ease of synthetic modification of oripavine to produce other narcotics (by either direct or indirect routes via thebaineThebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...
), the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
's Expert Committee on Drug Dependence recommended in 2003 that oripavine be controlled under Schedule I of the 1961 Single Convention on Narcotic Drugs
Single Convention on Narcotic Drugs
The Single Convention on Narcotic Drugs of 1961 is an international treaty to prohibit production and supply of specific drugs and of drugs with similar effects except under licence for specific purposes, such as medical treatment and research...
. On March 14, 2007, the United Nations
United Nations
The United Nations is an international organization whose stated aims are facilitating cooperation in international law, international security, economic development, social progress, human rights, and achievement of world peace...
Commission on Narcotic Drugs
Commission on Narcotic Drugs
The Commission on Narcotic Drugs is the central drug policy-making body within the United Nations system. Its predecessor, the Advisory Committee on the Traffic in Opium and Other Dangerous Drugs, was established by the first Assembly of the League of Nations on December 15, 1920...
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
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
by default as a thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...
derivative, although it was not explicitly listed. However, as a member state under the 1961 Single Convention on Narcotic Drugs
Single Convention on Narcotic Drugs
The Single Convention on Narcotic Drugs of 1961 is an international treaty to prohibit production and supply of specific drugs and of drugs with similar effects except under licence for specific purposes, such as medical treatment and research...
, the US was obliged to specifically control the substance under the Controlled Substances Act
Controlled Substances Act
The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
following its international control by the UN Commission on Narcotic Drugs. On September 24, 2007, the Drug Enforcement Administration
Drug Enforcement Administration
The Drug Enforcement Administration is a federal law enforcement agency under the United States Department of Justice, tasked with combating drug smuggling and use within the United States...
formally added oripavine to Schedule II.