Saturday, December 8, 2012
A Look at the Morphinan Structure Activity Relationships of Six Popular Opiates
The terms opiate and opioid are often used interchangeably, different authors define what is considered an opiate or an opioid with little consistency. The suffix "-iod" means like, hence opioids act like opiates. In general opiate refers to alkaloids found in the opium poppy that intereact with the body's endorphin receptors. Opioids are molecules that interact with the same receptors but are either fully synthetic (ie fentanyl), derived from the alkaloids found in opium and thus semi-synthetic (ie buprenorphine), and molecules from other plants that are distinct from morphine but nonetheless do interact with the opioid receptors (eg kratom). For the purposes of this blog, I define opiates are any molecules with only minor derivations on morphine. The following is a discussion of five common pharmaceutical narcotics and how they relate to the prototypical opiate, morphine. I consider codeine, hydromorphone, oxymorphone, hydrocodone and oxycodone all to be opiates. The most common changes to the morphine molecule involves:
1. Changing substituents at carbons 3 and 6. In morphine these are alcohol (-OH) groups.
2. Reduction of the double bond between carbons 7 and 8.
3. Addition of an alcohol (-OH). group at carbon 14.
4. Addition or changes to the group coming off the nitrogen, carbon #17.
Figure 1. Morphine with the carbon atoms numbered. Morphine is the primary alkaloid in opium.
Codeine is also found naturally in opium, and in (slightly) more enlightened countries is sold over the counter, though never without added acetaminophen (Tylenol) or acetylsalicylic acid (aspirin). Codeine is identical to morphine but has a methyl group attached to the oxygen on carbon #3. A carbon-oxygen-carbon grouping is known as an ether, thus codeine is 3-methyl ether morphine. This dramatically reduces the activity of codeine to only 10% of morphine.
Hydromorphone has two changes to the morphine molecule which increases its relative potency. The OH group at position 3 in morphine has the hydrogen removed, the oxygen is now double bonded to carbon 6. A carbon-oxygen double bond is known as a ketone ("key-tone"), thus the "-one" at the end of hydromorphone. The double bond between carbons 7 and 8 has been reduced to a single bond, by adding two hydrogen atoms (H not shown). This should make the molecule "dihydro-morphin-one," due to the addition of two hydrogen molecules (dihydro) and the oxidation of the OH group at carbon 6 to a ketone (morph-INE to morph-ONE). However the name is derived not from the double bond between carbon's 7 and 8, but for the atom bonded to carbon 14. In this case hydromorphone retains the same configuration as morphine, a single H at carbon 14.
Oxymorphone has the same two changes to the morphine molecule as hydromorphone, but also has an OH group attached to carbon 14 in place of the hydrogen in morphine. This increases the potency and is the reason the name is OXY-morph-ONE. The oxy prefix refers to the OH on carbon 14, and the one suffix refers to the change at carbon 6.
Both oxycodone and hydrocodone involve the same changes to the morphine molecule as oxymorphone and hydromorphone, but include the methyl (-CH3) group attached to the 3rd carbon just like codeine.
The changes to the morphine structure can be summarized as follows:
A. Addition of a methyl group to the oxygen on carbon 3. Creates a methyl-3-ether linkage. Reduces potency.
B. Alcohol group (-OH) on carbon 6 oxidized to a double bonded ketone (=O). Increases potency.
C. Hydrogenation (two H atoms are added) of double bond between carbons 7 and 8. Increases potency.
D. Substitution of an alcohol group (-OH) for the hydrogen at carbon 14. Increases potency.
Opiate Changes to Morphine Brand Names
Morphine - MS Contin
Codeine A Paramol, Tylenol 3
Hydromorphone B, C Dilaudid, Palladone
Oxymorphone B, C, D Opana, Numorphan, Numorphone
Hydrocodone A, B, C Vicodin, Lortab
Oxycodone A, B, C, D Oxycontin, Percocet, (More here)
Oxycodone is an example of all four changes to the basic morphine structure. A decreases the potency, while B, C and D increase the potency. The net result is a molecule slightly more potent than morphine, though far less potent than oxymorphone.