What do each of the 17 positions on the morphine carbon skeleton contribute to Structure-Activity Relationship and how?


Apr 18, 2019
. . . and how are they modified by which semi-synthetic opioids is my main question. What I was looking for in Duck Duck Go and not finding was a giant chart but, naturally, any information, especially about those aside from 1, 3, 6, 7, 8, and 14, is very much appreciated, so let it rip as I am sure I do not know everything there is to know about 3, 6 and the others listed.
also what was each of the classes of synthetics and their members intended/optimised to mimic and which features are totally unrelated and to what percentage they are truly morphinomimetic in the strict sense of the word and to what extent are truly novel.
I have always been very much interested in the history of pharmacology, pharmacy, toxicology, and medicinal chemistry and any relevant or tangentially-related details are very much appreciated too.


Jul 3, 2009
5: Metopon (5-Methyl-Hydromorphone is less potent than hydromorphone, but possesses a longer half-life

4: Removal of the 4,5-epoxy group results in racemorphan. The L-isomer ("levorphanol") is apparently more potent than morphine, but less selective for the MOR, also acting on KOR, inhibiting monoamine transporters and acting as an NMDA antagonist to some extent. The D-isomer, dextrorphan ("DXO"), is an active metabolite of dextrometorphan. Compared to DXM, DXO is less active as a serotonin reuptake inhibitor, and significantly more active as an NMDA antagonist.

17: N-alkylation greatly affects the acitivity of any opioid. Allyl and Cyclopropylmethyl groups result in MOR antagonism (although combined with the 7,8-bridge in buprenorphine you get a partial agonist). An N-phenylethyl group results in roughly a tenfold increase in opioid strength ("N-Phenethylnormorphine"). Methylating the tertiary amine into a quaternary ammonium prevents an opioid from crossing the blood-brain barrier, which is why N-methylnaltrexone can be used as a peripherally acting opioid antagonist (a sort of "reverse loperamide", if you will) to treat opioid-induced constipation in opioid-dependent pain patients.


Moderator: N&PD
Staff member
Sep 14, 2009
streets of simcity
this is kind of a silly question, every carbon contributes to the overall 3d structure, conformations that bind better to the mu receptor have stronger activity as analgesics. there are many reviews out there that go over "classical" opioid SAR

to what percentage they are truly morphinomimetic in the strict sense of the word and to what extent are truly novel.
0% and 100% resp.