The medical uses of morphine alkaloids have been known at least since the seventeenth century, when crude extracts of the opium poppy, papaver somniferum, were used for the relief of pain. Morphine was the first pure alkaloid to be isolated from the poppy, but its close relative, codeine, also occurs naturally. Codeine, which is simply the methyl ether of morphine and is converted to morphine in the body, is used in prescription cough medicines and as an analgesic. Heroin, another close relative of morphine, does not occur naturally but is synthesised by diacetylation of morphine.
Chemical investigations into the structure of morphine occupied some of the finest chemical minds of the nineteenth and early twentieth centuries, but it was not until 1924 that the puzzle was finally solved by Robert Robinson. The key reaction used to establish structure was the Hofmann elimination.
Morphine and its relatives are extremely useful pharmaceuticals agents, yet they also pose and enormous social problem because of their addictive properties. Much effort has therefore gone into understanding how morphine works and into developing modified morphine analogs that retain the analgesic activity but don’t cause physical dependence. Our present understanding is that morphine binds to opiate receptor sites in the brain. It doesn’t interfere with the transmission of a pain signal to the brain but rather changes the brains reception of the signal.
Hundreds of morphine like molecules have been synthesized and tested for their analgesic properties. Research has shown that not all the complex framework of morphine is necessary for biological activity. According to the “morphine rule,” biological activity requires: (1) an aromatic ring attached to (2) a quaternary carbon atom and (3) a tertiary amine situated (4) two carbon atoms further away.
Merperidine (Demerol), a widely used analgesic, and methadone, a substance used in the treatment of heroin addiction, are two compounds that fit the morphine rule.