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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").

Friday, July 15, 2011

Structural Modifications & Activity In The Mophine-Codeine Family



Epoxymorphinan Compounds QSAR

The images at the bottom of the page may be referenced as needed. For the "alterations to morphine and codeine" section, figures A and B represent several of the modifications I cover. Click on any image to enlarge. Feel free to use the images, but please include attribution.

Note: The 3-HO (phenolic hydroxyl) is vital for potent activity. Masking or replacing it with any substitution results in a reduction in effect. In stark contrast, modifications at 6 on the alcoholic ring produce an increase in potency. As a basic rule of thumb, a 3-HO potentiates, while a 6-HO reduces.

Morphine Molecule w/ Positional Numbering

Alterations to Morphine (See Image A for Visual)

3-Etherification - Reduces opioid potency by about 10-12x (morphine ethers bind less readily than phenols). Increases oral absorbtion, as ethers are more resistant to first pass metabolism. Result: favorable oral bioavailability (Morphine to Codeine, Oxycodone to Oxymorphone).

3 and 6 Esterification - Increase in potency (due to increased lipid solubility - which allows more morphine to reach the brain) Result: Rapid and complete CNS penetration, hence the 'rush'. Heroin is 2x stronger than morphine due to the fact heroin is essentially a faster acting & lipid soluble prodrug for the delivery of morphine and two active morphine analogues. Other esters include nicomorphine, dipropanoylmorphine, and dibenzoylmorphine.

Note: Selective esterification of 3 reduces activity to nearly zero. However selective esterification at 6 produces a greater potency - 6-acetylmorphine (a major active metabolite of heroin)

Saturation of the 7,8 double bond produces a modest increase in activity, a longer duration of action, and possibly a slight boost in oral bioavailability - Dihydromorphine

Note: Saturation of the 7,8 bond with the presence of substitutions at 6 produces the most significant increases in potency. (Dihydromorphine to Hydromorphone, Dihydrocodeine to Hydrocodone)

A combination of 7,8 saturation and 6-oxygenation increases potency 6 or 7-fold (i.e. hydromorphone). Changing the 14-H to a 14-OH affords a further increase to 10-fold morphine (i.e. oxymorphone). Such oxidation of 6 to a ketone reduces potency unless the 7,8 double bond is first reduced.

Substitutions of 6-HO with an ether, ester, hydrogen, or chlorine increase activity moderately to significantly. Placement of a methyl ether here produces hererocodeine - the reversed ester isomer of codeine - which is 6x stronger than morphine and 72x stronger than codeine. Saturating the 7,8 double bond in this case increases potency further.

Reduction of the 6-hydroxyl when 7,8 is saturated produces a compound 10x more potent than morphine (i.e. desoxydihydromorphine, or 'desomorphine').

Replacing the N-methyl group with an N-phenethyl yields N-phenethylnormorphine, a compound 18x stronger than morphine. Further substituting the 6-HO with a 6-methylene yields a dramatic increase to over 1,400x as strong as morphine.

Removal of the 4,5 ether chain will reduce activity unless a 6 substituent & 7,8 double bond are not present - In such conditions, the morphine (or epoxymorphinan) family becomes the morphinan family.

Image A

Alterations to Codeine (See Image B)

Most of these substitutions (at least where applicable) apply in an analogous way to codeine:

Saturation of the 7,8 double bond produces a modest increase in activity, a longer duration of action, and possibly a slight boost in oral bioavailability - Dihydrocodeine.

Saturation of the 7,8 bond with the presence of substitutions at 6 produces the most significant increases in potency. For instance with the 7,8 saturated, oxydation of 6 to a ketone produces hydrocodone, a 6x increase from codeine. Adding an OH at 14 increases potency further yielding oxycodone, a 10x increase from codeine.

Substitutions of 6-HO with an ether, ester, hydrogen, or chlorine increase activity moderately to significantly. Demethylation of 3 converts codeine back to morphine (10x increase). Or, substitution of an ethyl ether at 3 creates ethylmorphine, which is practically equipotent to codeine.

Image B

Other Modifications:

As a general rule; Substitutions of the N-Methyl substituent of morphine type opioids may yield mu-antagonist compounds or partial or mixed agonist/antagonist compounds, depending on the substitution - naloxone is nearly identical to oxymorphone but substitutes the N-Methyl feature with an N-Allyl, resulting in antagonist activity. Buprenorphine has the structural characteristics of the highly potent agonist bentley compounds, however the N-Methyl group is replaced with a cyclopropyl group, lending it mixed agonist/antagonist properties.

N-Methyl substitution in some cases may cause a significant increase in agonist activity; N-phenethyl subtitutions in many cases increase potency - N-phenethylnormorphine, N-phenethyl-14-ethoxymotophon, phenomorphan, and the hydromorphinol analogue RAM-378 - All highly potent mu-opioid agonists ranging from 4x to 60x the potency of morphine.

** Research suggests that 3 O-methylation of morphine-class compounds (as in morphine to codeine) reduce potency without altering ratios of receptor selectivity.


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