For millennia mankind has sought methods of alleviating pain. Though many remedies ultimately prove to be folklore or pseudoscience, some plants have been found even in ancient times to have an analgesic, or pain-relieving, property. Indeed it was from a plant that the now-ubiquitous aspirin was first derived. But one of the most potent drugs available in the modern pharmacopeia also derives from a humble plant. If you have ever had the misfortune of needing surgery there is a good chance that you too have benefited from the biochemical properties of this Molecule of the Week: morphine.

Morphine falls into a broad class of molecules called the opiates, and it is the prime constituent of the namesake, opium. All opiates are chemically similar, often sharing the general fused-ring motif seen in Figure 1.

Chemically, morphine is termed 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol, though it is unlikely you will ever find a chemist calling it by its proper name - even seasoned organosynthetic chemists find such unwieldy names somewhat useless in practice.

There are several structual aspects of morphine that interest chemists (it will be helpful to glance back at Figure 1 while reading).

First, morphine posseses a rather complex fused-ring system, and more specifically contains a carbon at which three distinct rings are joined. While certainly not too unusual in "natural products" (molecules produced by living organisms), the presence of such a system poses a challenge for chemists wishing to prepare morphine from "scratch."

Second, morphine has a high degree of asymmetry: if you held a mirror up to the molecule and compared the image in the mirror to the authentic molecule you would find that they are definitely not identical. Molecules shaped in such a manner are said to be chiral.

(If you look closely you can find individual carbon centers that confer this asymmetry - the ring carbon attached directly to the nitrogen is one such carbon, called a chiral center. There are five distinct chiral centers in morphine; try to spot all five. What do all of them have in common? [Answer: note 1])

Chiral molecules are almost always more difficult to make than achiral molecules (molecules that possess enough symmetry that their mirror images can be superimposed directly on the original molecule). To introduce asymmetry chemists must resort to special "tricks" such as using an already purified chiral material as a precursor (i.e. chiral amino acids purified from bacteria) or using a chiral catalyst that causes the reaction that forms one mirror image to occur faster than the reation that forms the opposite image. To this day so-called asymmetric synthesis is a hot topic in the scientific literature.

Given the structuraly and synthetically interesting properties described above, and the potent pharmacological properties discussed below, it should come as no surprise that morphine has been heavily studied by organic and biochemists. (A literature search done by the author revealed no fewer than 25,000 articles published in the chemical literature about morphine and its chemical relatives. And this does not include the great many articles that discuss its medical and narcotic properties!)

Among the papers published in recent years are several total syntheses that grapple with the complexities described earlier. If you are an advanced student (at least having completed a full course in organic chemistry) you may enjoy reading the 23 step synthesis described by Taber et al. (note 2) as an example of how chemists approach the in vitro preparation of a sophisticated natural product.

In addition to its synthetically interesting aspects morphine provides a good example of a weak organic base, owing primarily to the tertiary amine NR₃ (where "R" is used to generically represent an organic carbon group).

The fact that the neutral amine can be protonated by acid to give a positively charged ammonium (NR₃H⁺) group is neatly illustrated by solubility. At neutral pH (as in ordinary water) morphine is only modestly water-soluble due to the bulky and hydrophobic (literally, "water-fearing") organic groups. However, at low pH (as in aqueous acid, such as in the stomach), the acquisition of a positive charge upon protonation greatly reduces hydrophobicity and makes the compound very soluble. This property is exploited when morphine (and its more commonly orally-administered relative codeine [note 3]) are given to patients in pill-form: the drug readily dissolves on contact with stomach acid.

Long before chemists had even begun to map out the series of reactions needed to transform smaller building blocks into the complex substance depicted in Figure 1 a lowly plant, the opium poppy, was producing morphine in the efficient chemical factories that comprise its cells.

As stated in the introduction, morphine is a potent pain reliever, and has been known as such all the way back to at least the time of the Ancient Greeks (roughly 800 BCE to 400 BCE) (note 4). In modern day, morphine is commercially manufactured (and, due to its potential for abuse and chemical conversion into more dangerous opiates, heavily regulated) as a prescription drug.

The mechanism by which morphine and other opioids (the broader category of which the opiates are part) induce their desired effects is at least somewhat well understood. Cells in the nervous system, including brain cells, are endowed with protein structures on their surface that are fittingly called opioid receptors. After many years of research neurophysiologists and biochemists have learned that the brain produces on its own a class of molecules called endorphins that bind to opioid receptors and cause an increase in activity of another biochemical, dopamine (Figure 2), which is believed to be broadly involved in feelings of pleasure and alleviation of pain.

It is worth noting that even though morphine binds and activates the opioid receptors ordinarily reserved for endorphins, the two share almost no chemical similarity: whereas morphine is the relatively small molecule previously depicted, endorphins are peptides, or short proteins, with radically different chemical groups, size, shape, and reactivity. This goes to show that just because two chemicals have mechanistically similar biological effects it does not follow that they are close chemically.