Analgesic activity, opiate

The identification of the morphine receptor spurred an effort in many laboratories to find an endogenous agonist for which that receptor was normally intended. Ultimately, a pair of pentapeptides that bound quite tightly to opiate receptors were isolated from mammalian brains. These peptides, called enkephalins (2, 3), show many of the activities of synthetic opiates in isolated organ systems. They do in fact show analgesic activity when injected directly into the brain. It is thought that lack of activity by other routes of administration is due to their rapid inactivation by peptide cleaving enzymes. 

Morphine and related opiates are known to suppress the cough reflex these compounds have thus been used extensively in antitussive preparations. Since this activity is not directly related to the analgesic potency, the ideal agent is one that has much reduced analgesic activity and thus, presumably, lower addiction potential. The weak analgesic codeine (4) is... 

Meperidine (Schedule II) is a synthetic analgesic with opiate activity. It has 10-20% of the potency of morphine with all of the addictive side effects. It has a rapid onset of action and duration which makes its useful for relieving the pain associated with labor or as a preanesthetic before surgery. Its biotransformation produces normeperidine which has been associated with seizures. It was a botched clandestine attempt to synthesize a meperidine modification which produced the toxic drug that induced parkinson-type destruction of DA neurons in its users. 

Pless, J., Bauer, W., Cardinaux, F., Closse, A., Hauser, D., Hugenin, R., Roemer, D., Buescher, H.-H., Hill, R.C. Synthesis, opiate receptor binding and analgesic activity of enkephalin analogues, Helv. Chim. Acta 1979, 62, 398-411. 

Like morphine, most analgesically active morphinans bear an oxygen function, usually as hydroxyl, in position C-3. The presence of 3-OH or 3-OAc invariably leads to a significant enhancement of opiate activity in these series, whereas 3-OMe affords, at best, a modest activity increase/81 Other 3-position substituents significantly reduce or abolish activity. 

The opiates are perhaps the oldest drugs known to man. Opium contains a complex mixture of almost 25 alkaloids. The principal alkaloid in the mixture, and the one responsible for analgesic activity, is morphine, 11. Pure morphine is especially good for treating dull, constant pain, and periodic pain. Unfortunately, it has a large number of side effects, which include the depression of the respiratory center, excitation, nausea, euphoria, dependence, and others [6]. 

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