Morphine

Many medicinal agents important to life are combinations of mirror-image twins called chiral compounds. These twins may look very similar, yet their biological makeup might differ significantly. In other words, the pharmacokinetic and pharmacodynamic profiles of the individual enantiomers that make up a racemic chiral medication might drastically vary. The Chiral Molecule of the Week #cMOTW is an effort to highlight significant chiral compounds with therapeutic value. Follow us for more ……

Nature is not even handed. Unichirality – is hallmark of many molecules from nature.

The opioid agent morphine is a millennia-old-unichiral drug; Opium powder is the  dried juice from the unripe  seed capsule of the poppy Papaver somniferum; analgesic and euphoric.

Chirality and biological activity

Morphine has a highly demanding chemical structure. It is a pentacyclic 3°amine (alkaloid) with 5 stereogenic centers and exists in 32 stereoisomeric forms (2ⁿ = 2⁵= 32 stereoisomers; n being number of stereogenic centers). But the desired analgesic activity resides exclusively in the natural product, the (-)-enantiomer with the configuration ((5R,6S,9R,13S,14R). (In the structure below stereogenic carbons are numbered in red font and configuration assigned in brackets.)

Nomenclature

7,8-didehydro-4,5-epoxy-17-morphinan-3,6α diol

It is interesting to note that when we humans try to synthesize chiral molecules, at large, we end up in racemic mixtures. To make enantiopure molecules one need to employ specialized tools viz. enantioselective catalysts/synthesis  and  for developing such innovative and breakthrough tools scientists are awarded Nobel prizes. For instance, Nobel prizes in Chemistry are awarded  in 2001 (https://www.nobelprize.org/prizes/chemistry/2021/press-release/) and again in 2021, after a decade, (https://www.nobelprize.org/prizes/chemistry/2021/press-release/) for developing such ingenious tools  But nature make enantiopure molecules elegantly, neatly, and silently in an eco-friendly environment with so much ease. Nature is incredible!!!.

Therapeutic category

Narcotic analgesic and sedative

Exercise

Construct molecular model of morphine and learn to assign absolute configuration to the stereogenic centers as per CIP rule.

References

Joseph Gal in Chirality in drug research. Edited by Eric Francotte, W. Lindner. Weinheim: Wiley-VCH.  Page 3-25, 2006. ISBN 978-3-527-60943-7.

Wainer, l. W., & Drayer, D. E., Eds. Drug stereochemistry and Pharmacology: Marcel-Dekker, New York,1988.

Ernest L. Eliel Samuel H. Wilen, Stereochemistry of Organic Compounds, John Wiley and sons, New York.1994. ISBN 0-471-01670-5

Chiral drugs. Wikipedia, Wikipedia Foundation, 27/01/2022.  https://en.wikipedia.org/wiki/Chiral_drugs

“The handed world“, https://chiralpedia.com/blog/the-handed-world/.

“Chiral twins – Identical? … But not really!”,  https://chiralpedia.com/blog/ chiral-twins-identical-but-not-really/.

Harkishan Singh and V.K. Kapoor. Medicinal chemistry and pharmaceutical chemistry, Vallabh Prakashan, New Delhi, 2012.