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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, February 18, 2011

Modifications in the Morphine/Codeine Series (Summary)

Phenolic HO (in the morphine series):

Etherification of the phenolic hydroxyl: A methyl ether reduces activity 10-fold, enhances oral efficacy. Ethyl ethers have roughly the same effect. Morphine to codeine, dihydromorphine to dihydrocodeine, or morphine to ethylmorphine.

Esterification of the phenolic hydroxyl increases lipophilicity but drastically reduces activity to sub-codeine levels.

Alcoholic HO (in the morphine-codeine series):

Etherification of morphine's alcoholic hydroxyl with a methyl or ethyl increases potency by 4-6x. May also increase toxicity.

In most cases, esterification of morphine's alcoholic hydroxyl increases potency by 2-4x. Possible esters include acetate, nicotinate, propionate, or benzoyl. One exception is with the bulky benzyl myristyl ester - reducing activity significantly.

Introduction of a 6-chlorine increases activity by 8-10x.

Introduction of a 6-hydrogen increases activity by ~10x.

Removal of the 6-alcohol increases activity by 8-10x. Increased lipophilicity and much shorter duration.

3 or 6 HO (in the morphine-codeine series):

Esterification of either the 3 or 6 hydroxyl decreases polarity and renders morphine compounds more lipophilic and faster acting. However; masking the phenolic hydroxyl decreases activity significantly, while doing the same to the 6-hydroxyl increases activity by several fold. 

Hydrogenation of the 7,8 double bond of morphine or codeine increases activity by 1.5-2-fold. Increases intrinsic efficacy at the mu receptor. Increases duration of action. Morphine to dihydromorphine, codeine to dihydrocodeine.

Alcoholic HO (in the dihydromorphine/dihydrocodeine series):

Oxygenation of the alcoholic hydroxyl to a ketone increases activity by around 4-fold.

Introduction of a 6-methylene increases activity by at least 40x (to around ~80x morphine).

5-Position modification (in the dihydromorphinone series):

methylation of the furan/alcoholic 5-position reduces sedation, toxicity and dependence liability without a significant affect on activity (the result is stil 2-3x stronger than morphine). Oral efficacy is increased.

14-Position (in the dihydro-6-ketone series):

Introducting a hydroxyl to the quartenary 14-position increases activity slightly while reducing antitussive properties. This also creates a tertiary alcohol. Hydrocodone to oxycodone, hydromorphone to oxymorphone.

The tertiary alcohol (C14) can be acetylated, just like the 6-hydroxyl - producing an increase in activity.

Alicyclic Ring (in the morphine-codeine series):

The 7,8 double bond can be hydrogenated - increases activity by 1.5-2x. Increases intrinsic efficacy. Increases duration of action. Dihydromorphine is 1.5-2x stronger than morphine and longer acting. The same goes for dihydrocodeine. Both drugs are prototype to their own large series' of dihydro analogues.

With a morphine 6-ester such as acetylmorphine: Hydrogenation of the the alicyclic ring (i.e. 6,7 or 7,8 bond) decreases activity. With acetylcodeine however, 7,8 hydrogenation increases activity, (acetyldihydrocodeine).

Removal of Functional Groups (dihydromorphine series):

When the 7,8 double bond is hydrogenated (i.e. dihydromorphine): Removal of the alcoholic hydroxyl increases activity by roughly 5x - or about 8-10x than of morphine. Increased lipophilicity. Rapid onset but shorter duration of action.

When the 7,8 double bond is hydrogenated (i.e. dihydromorphine): Removal of the furan oxygen bridge (and the alcoholic hydroxyl) yields a prototypic 4-ring morphinan compound; with increased activity, increased lipophilicity, and a longer duration of action.

Nitrogen Substitutions (general):

Removal of the N-methyl group off the piperidine ring decreases activity. A tertiary nitrogen is essential. 
N-methyl substitutions are variable effect. Allyl substitutions drastically reduce activity and create opioid antagonists. Alkyl substitutions reduce activity. 

An N-alkyl substituent consisting of a 3-carbon chain (with or without an additional methyl group) results in antagonist activity. This is avoided by utilizing alkyls with greater than 3, or less than 3, carbons.


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