About

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").

Thursday, December 1, 2011

Review of the 3 and 6 Esters of Morphine

Chemically speaking, the less polar a compound is, the more lipophilic it will be. Morphine has three polar groups; a 3 and a 6 hydroxyl, and an N-methyl. Effect on potency aside - masking a polar group with a subtituent results in an improved ability to cross the blood-brain barrier.

Take 6-acetylmorphine (6-AM) for instance, where the 6-hydroxyl has been masked by an acetyl ester. 6-AM therefore contains only 2 polar groups, rendering it lipophilic. The molecule reaches the brain more quickly and in higher volume than does morphine alone, and is therefore more potent. Further adding to its potency however is the fact that the 6-acetyl substituent increases its activity at the mu receptor, and is believed to reach a third binding site of the mu receptor. 6-AM is at least 4x as potent as morphine as a narcotic and has a higher affinity for the mu receptor.

As a side note: Not only are lipophilic opioids stronger and faster acting, but they reach the brain tissues and spinal cord in greater relative portions, and act more selectively on the central nervous system, therefore producing less constipation & itching, with more analgesia, sedation and euphoria. In short, lipophilic compounds are drawn to the brain like a magnet, while hydrophilic compounds linger outside of the brain, in the bloodstream and peripheral organs. Lipophilic opioids generally have a "cleaner" feel, while polar opioids like morphine feel less so, producing itching, flushing and 'body-load' - for instance, the heavy feeling in the gut and the deep "leg-burn" of a morphine buzz; as opposed to the serene, cerebral high of heroin, dilaudid or fentanyl.

Now let's consider diacetylmorphine, i.e. heroin. Heroin has both the 3 and 6 hydroxyl groups masked with acetyl groups. It is less polar than both morphine & 6-acetylmorphine and therefore reaches the brain very rapidly and in high volume, making it more potent than morphine. Unlike 6-acetylmorphine however, diacetylmorphine binds poorly to receptors because the essential 3-hydroxyl is masked. So although it is less polar and faster acting, it is less potent than 6-acetylmorphine as an opioid The 3-acetyl group is removed for maximum activity. Heroin is about twice as potent as morphine by weight and half as potent as 6-acetylmorphine, while it is faster acting than both.

Both heroin and 6-acetylmorphine are metabolized to morphine by enzymes in the blood and brain - heroin obviously requires 2-steps, while 6-acetylmorphine becomes morphine in one step. This process occurs over the first several minutes following venous injection or otherwise systemic absorbtion.

There are many other esters of morphine which have been synthesized at some point, and all of these share similar properties. They are all lipophilic drugs which are faster acting and stronger than morphine. Nicomorphine is the 3,6 nicotinate ester of morphine and is used medicinally as a potent painkiller mainly in Europe.

Dipropanoylmorphine: An Obscure Morphine Ester:

Semi synthetic opioid of the morphine type. Dipropanoylmorphine is a heroin analogue - specifically a 3,6 propionyl ester of morphine.

Discovered more recently than other morphine esters (in 1974) therefore its history & use dates back no longer than fentanyl.

Rarely used medicinally, if at all. 3-4x as potent as morphine due to its high lipophilicity. Longer lasting than morphine and heroin due to the presence of two propionyl groups which are broken down more slowly than the acetyl groups of heroin.

Effects are similar to heroin, and include analgesia, euphoria, sedation, itching, nausea, constipation peripheral vasodilation and respiratory depression. Its effects last 3-6 hours.

There exists a number of heroin-analogues which have never been marketed for medical use, and had not ever been used in humans until appearing on the illicit opiate market, The following are 3,6 morphine diesters as well:

Dihydroheroin:

 A semi-synthetic opioid of the morphine class. It is an analogue of heroin, where the 7,8 double bond has been saturated. It is about as potent as heroin with a longer duration of action. Dihydroheroin is immediately metabolized by plasma esterase enzymes to the much more active 6-acetyldihydromorphine and further dihydromorphine; both of which are potent opioid agonists. Effects are similar to heroin, but with a longer duration than either morphine or heroin and a possibly slower onset.

Dibenzoylmorphine:

Developed during the early 20th century in the years following the US Harrison Act and similar criminal laws passed in a handful of nations - which were the first steps in criminalizing the non-medical use of heroin and other narcotics. First synthesized in the United Kingdom. Dibenzoylmorphine was the most common morphine ester used as a heroin substitute. It serves as a fast acting prodrug for its monoester 6-benzoylmorphine and morphine, and is expected to have virtually identical effects to heroin - including an intense onset or "rush" when injected intravenously.

Acetylpropionylmorphine:

Acetylpropionylmorphine is the 3-acetyl, 6-propionyl ester of morphine. It was synthesized in Great Britain and appeared as a heroin substitute around the same time as dibenzoylmorphine. It serves as a fast acting prodrug for 6-propionylmorphine and its effects too are virtually identical to heroin - including the initial IV "rush".

1 comment:

  1. Hi

    Are the ester's of morphine (Other than the acetyl ester versions.) all the same strength as diamorphine/heroin but with varying degrees of duration or are some alot stronger than Diamorphine/heroin?

    ReplyDelete