Oxymorphone and Oxycodone

Figure 1

The Classes of Opioid Compounds, Based on Structure

Figure 1

The Classes of Opioid Compounds, Based on Structure

Addictive Behavior Not Youtube

The morphine molecule has a single nitrogen atom. The substituent on the nitrogen in these series of opiates can have major effects on activity. Morphine and most of the mu agonists contain a methyl (CH3-) group on the nitrogen, but a number of other compounds with different substituents have been developed. Replacing the methyl group with an allyl (-CH2CH = CH22) or methylcy-clopropyl (-CH2CHCH2CH2) group does not have much effect upon the ability of the compound to bind to opioid receptors, but it markedly changes what happens when they do bind. For example, oxymorphone, with its methyl group on the nitro gen, is a clinically useful analgesic many times more potent than morphine. Replacing the methyl group with an allyl group produces NALOXONE. Naloxone is an antagonist, a drug that blocks or reverses the actions of other opiates. Clinically, naloxone is used as an antidote to opiate overdose. This shows how simple changes can profoundly influence the pharmacology of these agents.

Further investigations revealed that Ring C of morphine can be eliminated, enabling use of the benzomorphans—many of which are potent analgesics. The major drug in this group is pentazocine (Talwin). Even simpler structures produce potent

Pentazocine Structure

Figure 2

The Morphine Molecule and Some Widely Used Related Compounds, Based on Region of the Molecule

Figure 2

The Morphine Molecule and Some Widely Used Related Compounds, Based on Region of the Molecule analgesics, such as methadone. The phe-nylpiperidines comprise another large group of opioids. The first of these to be used clinically was meperidine, which was first prescribed in 1939 and which still is extensively used. Modifications of the phenylpiperidine structure led to a subgroup of drugs, with fentanyl as a prototype. Fentanyl is approximately 80-fold more potent than morphine, but its very short duration of action requires continual infusions. An advantage is that once the infusion is discontinued, the effects of the drug clear rapidly. This ability to quickly turn on or off the drug's actions, along with its great potency, has made this agent a valuable tool in anesthesia. Recently, this high potency has been exploited to develop skin patches which give a constant release of fentanyl into the body as the drug is absorbed through the skin. Other agents within this series, such as sufentanil and alfentanil, are even more potent than fentanyl. Two other members of this series, loperamide and diphenoxylate, have activity but very poor solubility. This property has led to


Selected Opioid Peptides





Dynorphin A



Dynorphin B












their use as antidiarrheal agents since they cannot be made soluble and injected and are therefore less likely to be abused.

Together, these structure activity studies reveal that the basic requirements needed for opioid activity are quite simple. However, the wide variety of structures becomes even more intriguing since morphine and the other opioids act within the brain by mimicking naturally occurring peptides—the endogenous opioids. The enkephalins were the first such naturally occurring substances to be isolated and sequenced (Table 2). Initially, these results were somewhat confusing since the two enkepha-lins—both pentapeptides—contain the identical first four amino acids and differ only at the fifth. The complexity of these peptides became more clear with the subsequent isolation and characterization of ^-endorphin, a 31 amino acid peptide derived from a larger protein, which also gives rise to active compounds, including ACTH and a-MSH. The first five amino acids in ^-endorphin are identical to [met5]enkephalin, but [met]enkephalin and ^-endorphin derive from different gene products. There are also a series of compounds containing the sequence of [Leu5]enkephalin, including dynorphin A, dynorphin B and a-neoendorphin. All these compounds (the ENKEPHALINS, ENDORPHINS, and dymorphine) have distinct genes and are expressed independently from one another. Thus, they comprise a family of similar, but discrete Neurotransmitters.

The opioid peptides are only now becoming important clinically. A major difficulty in the use of peptides is the fact that they are broken down when taken by mouth, and thus, most have very limited oral activity. However, new derivatives specifically designed to be more stable have been developed, which will provide new leads. The enkephalins are potent at delta receptors, and many of their derivatives are delta-selective. Some of the more recent derivatives label delta receptors more than 10,000fold more selectively than others. Yet other pep-tides are very much like morphine in terms of their pharmacology and receptor binding. Finally, pep-tides with opioid actions are now being identified in a variety of other tissues; for example, toad skin has dermorphin, a potent and stable opioid peptide.

(SEE ALSO: Addiction: Concepts and Definitions; Opioid Complications and Withdrawal; Pain)


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Increasing use of opioid analgesics has not exacerbated ADDICTION (2000). The Brown University Digest of Addiction Theory and Application, 19, 1.

Jaffe, J. H. (1990). Drug addiction and drug abuse. In A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

Jaffe, J. H., & Martin, W. R. (1990). Opioid analgesics and antagonists. In: A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

Magill-Lewis, J. (2000). How should opioids be converted? Pharmacists differ on approach. Drug Topics, 144, 53.

Thorns, A., & Sykes, N. (2000). Opioid use in last week of life and implications for end-of-life decision-making. The Lancet, 356, 398.

Will opium rear its smoky head yet again? (1999). Psychopharmacology Update, 10, 3.

Defeat Drugs and Live Free

Defeat Drugs and Live Free

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