Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Saturday, October 15, 2011

All About the Bentley Compounds

It may not seem like much, but trust me, I've worked many hours to piece together enough information for a relatively minor overview of the Bentley family of opioids; specifically focusing on Etorphine, Buprenorphine & Dihydroetorphine. Short of scouring the depths of the web for days (with dozens of sources), you won't find much of this information so conveniently summarized - anywhere else. Consider it a few steps up from Wiki. Any sources I've used relating to the Bentley's are listed on my reference & further reading page.

The Bentley Compounds

Opioid analgesics were a major focus of research during the late 1950's and early 60's. Several years before Paul Janssen and his colleagues would discover the fentanyl family, Kenneth Bentley and his team identified some 200 compounds derived from thebaine, known as the orvinols. The orvinols are popularly referred to as the bentley compounds. The bentley's are built off of the O-demethylated product of thebaine - oripavine. Oripavine occurs naturally in poppy straw concentrate, as a degradation product of thebaine.

From Thebaine to Oripavine (Top)
Oripavine plus C-Bridge (Bottom)

Chemically, bentley compounds are 'diels alder' reacted adducts of thebaine, also derived from oripavine, the compound off which the orvinols are chemically built. They are molecularly known as the endoetheno-tetrahydro-oripavines. It is important to note that both thebaine and oripavine are phenanthrene opiate alkaloids of the epoxymorphinan type, with a similar structure to morphine and are considered semi-synthetic morphine-type opiates. However, they are unique from morphine in that they have an endoetheno bridge at the C-ring, and any one of a number of alcoholic substituents branching from C-7.

The bentley's include over 200 identified compounds, each with varying potency and activity. The more common compounds range in potency from several to several thousand times stronger than morphine. The intermediate orvinol structure differs from oripavine only with the addition of the C-bridge - it is roughly 40x more potent than morphine; and the addition of a C-7 substituent further increases its potency.

As with other morphinan opioids, a methyl group off of the tertiary nitrogen is ideal for mu-opioid efficacy. Most other nitrogen substitutions elicit major changes in intrinsic activity or binding affinity; changes include reduced agonist activity, zero agonist activity, partial agonist activity, or mixed agonist/antagonist activity.

Etorphine (Fact Overview)

Discovered in the early 1960's.

Effects similar to morphine. Analgesia, catatonia, constipation, respiratory depression, initial excitement, and sedation.

Takes effect within minutes of injection, peaks after 15 to 30 minutes. Analgesia and sedation last 30 to 60 minutes in animals.

Produces euphoria & reward. Presumed to have a high abuse & addiction liability in humans.

Very effective as a painkiller. 1,000 to 4,000x more potent than morphine as an analgesic, depending upon the clinical setting. A dose of 0.0025 to 0.01 mg (or 2.5ug to 10ug i.e. micrograms) would be roughly as active as 10mg morphine by injection. Lethal dose for an adult human will range from 30ug to 120ug.

One of the least subtype-selective opioid agonists in use.

High affinity for mu and kappa receptors, moderate affinity for delta receptor; agonist at all three.

Also referred to as 'M-99' or Immobilon in the veterinary setting. Used on large game animals as a tranquilizer and anaesthetic.

Because of its potency, M-99 is always supplied alongside its antidote, diprenorphine (or Revivon), an ultra potent opiate antagonist, and also a bentley compound. In case of human exposure, diprenorphine reverses an overdose.

International legislation barred etorphine for use in humans unfortunately. Its 7,8 dihydro derivative is currently used in humans, and is several times more potent. John Lewis, a former researcher with Bentley, has speculated that etorphine may have had success as a human product, had it been marketed differently:

Immobilon (i.e. Etorphine Hydrochloride)
"The popular scientific press were excited by news that doses of a few milligrams of etorphine could immobilize an elephant or rhinoceros. This turned out to be very bad publicity for etorphine for it convinced the World Health Organization (WHO) that etorphine was extremely dangerous and therefore should be controlled in Schedule 4 of the Single Convention, the most restrictive level of control. At about that time, fentanyl, a synthetic opiate of not dissimilar potency to etorphine was being developed by Paul Jannsen as an intravenous anesthetic for human use. Fentanyl and its analogs have been huge commercial successes whereas etorphine, which I’m sure could have been an equally successful clinical anesthetic, has had very modest sales as a veterinary anesthetic. I think we must conclude that etorphine arrived too early for the consumer marketing people of Reckitt to appreciate how it should be commercialized."

J. Lewis - Former Researcher with K W Bentley's Team - From his lecture at the 'Nathan B Eddy Award Ceremony' explaining the history of the Orvinols, i.e. Bentley Compounds

Dihydroetorphine (Fact Overview)

Ultra potent opioid agonist. Reletatively selective for the mu receptor, with high affinity and efficacy. 1,000 to 12,000x more potent than morphine and 2 to 13x more potent than etorphine, depending on the method of measure.

Elimination half life of 30-40 minutes (~38min); analgesia lasts 1-2 hours depending on ROA and dose - requiring dosing intervals of 1 to 3 hours when given in its traditional form.

Used as an analgesic in humans in China. Like bupe, DHE is poorly absorbed orally. It is given by injection, sublingual or buccally, or transdermally. Sublingual doses of 20 to 180 ug are fully analgesic and produce relatively mild side effects. DHE in a long acting transdermal patch has been shown to relieve pain for up to 32 hours with minimal side effects.

Produced potent reward & reinforcement in studies, but is believed to produce a lesser ratio of euphoria to analgesia than does morphine or heroin. Though it is obviously a more potent euphoriant than morphine by weight, it may carry a lower addiction liability in equivalent doses.

Reportedly has been used in opiate substitution therapy, with positive results.

Available in sublingual tablets of 20ug or 40ug. Or as solution for injection containing 20ug/ml dihydroetorphine hydrochloride. Transdermal patches available (dose range??)


In 1966, researchers had synthesized a compound which was reserved the name M6029. M6029 was an N-subtituted orvinol which would later become known as buprenorphine (i.e. bupe). Bupe was a typical bentley opioid, similar in structure to etorphine, but was substituted with a nitrogen-cyclopropylmethyl as opposed to the methyl. None the less, it produced potent antinociceptive effects, 33x stronger than morphine.

As it turned out, the CPM group of bupe created a mixed agonist antagonist - with partial agonist activity at the mu receptor, antagonist activity at the kappa receptor. Unlike other mixed agonist antagonists at the time, buprenorphine produced no dysphoria - while drugs such as pentazocine and butorphanol were agonists at the kappa receptor and thus likely to produce dysphoria, bupe was an antagonist at kappa receptors.

Also, being a bentley compound, bupe retained a significant deal of potency even with the N-CPM substituent. As a potent mu-receptor partial agonist; It activated the mu receptor in relatively miniscule doses, until reaching a plateau in dose-effect. In doses below the ceiling, it acted just as any potent full agonist would, but did so at a microgram dose. Only 0.3mg of IV bupe was equal to 10.0mg IV morphine in its pain relievieffectng . More recently it has been found that the ceiling for analgesia occurs at around 2 to 4mg of sublingual buprenorphine (or roughly 0.6 to 1.2mg IV). The ceiling for other agonist type subjective effects (euphoria, narcosis) occurs higher, ranging between 4mg and 32mg.


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