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.
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.
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.