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AGONISTS, ANTAGONISTS, AND PARTIAL AGONISTS

Some drugs have very complex actions and many drugs act at specific RECEPTOR, locations on the surface of a cell. All of the drugs that belong to the class of drugs called opioids act at opioid receptors on the surface of cells. Usually these cells are neurons, but there are also opioid receptors on white blood cells. Once a drug binds to a receptor, it can either turn it on (AGONIST) or do nothing (ANTAGONIST). Even if a compound does nothing once it binds to the receptor, it still blocks the site and prevents an active compound from binding to the receptor. The situation is much like a key in a lock; some keys fit into the lock but will not turn, and as long as they remain in the lock they prevent the insertion of keys that would turn the lock. Finally, there are drugs known as partial agonists; these compounds bind to the receptor and turn it on but not nearly as well as pure agonists.

Again, using the key analogy, these partial agonists will turn in the lock, but only with some jiggling, lowering the efficiency in opening the door. Pharmacologically, partial agonists have limited effects at the receptor, termed a ceiling effect. This means that increasing the dose further will not give a greater response. To further complicate understanding of these drug actions, it is important to recognize that the opioid receptors (and many other types of receptors as well) are actually families of similar but subtly different receptor types. Some opioids are agonists at one receptor type and partial agonists or even antagonists at another receptor type. These drugs are termed mixed agonist/antagonists and they can have complex pharmacological profiles. For this reason it can be difficult for pharmacists to determine conversion amounts (for example, to methadone) (Magill-Lewis, 2000).

RECEPTORS

Morphine and drugs with similar actions work through specific recognition sites, termed receptors, located on the outside of cells (see Table 1). A number of general classes of opioid receptors have now been identified and it is likely that even more will be discovered. The major types of opioid receptors have been designated mu, kappa, and delta. From the clinical perspective, the mu opioid receptors are the most important. This class, comprised of two subtypes, mu₁ and mu₂, have high affinity for morphine and most of the clinically used agents. Both mu subtypes mediate analgesia, but through different mechanisms and locations within the brain and spinal cord. Mu receptors have been implicated in euphoria and mu agonists have often been abused. Equally important, activation of mu receptors depresses respiration and inhibits gastrointestinal transit. In addition to analgesia, euphoria, respiratory depression, and decreased activity in the stomach, mu agonist opioids produce some actions that are clinically useful, such as cough suppression. However, most of their actions are considered unwanted side effects; for example, they affect endocrine function, constrict pupils, induce sweating, and cause nausea and vomiting. All mu agonist opioids also induce increasing tolerance and physical dependence in the user.

Kappa opioid receptors were defined using ketocyclazocine, an experimental benzomorphan derivative, and subsequently with dynorphin A, an endogenous opioid, which is believed to be the natural ligand for at least one of the kappa receptor subtypes. Morphine has relatively poor affinity for kappa receptors, but other drugs, such as pentazocine and nalbuphine (analgesics in clinical use), interact with kappa receptors quite effectively. The importance of kappa mechanisms in their actions have only recently been appreciated. The pharmacology of kappa receptors in humans has not been extensively studied; however, animal studies indicate that the kappa receptors also can relieve pain through receptor mechanisms distinct for each of the subtypes. Many of the clinically used drugs active at kappa receptor are mixed agonists/antagonists. Although they are agonists at kappa receptors, they are antagonists or partial agonists at mu receptors. In contrast to mu agonists, which can produce mood elevations and euphoria, drugs that activate kappa agonists appear to produce weird feelings and dysphoria.

The discovery of the enkephalins—endogenous peptides with opioid properties—soon led to the identification of delta receptors. The clinical pharmacology of delta receptors is not well known, primarily because so few agents have been tested in humans. Again, animal testing indicates an important role of delta receptors in analgesia, which is supported by a few studies with humans. However, there are no pure delta agonists clinically available yet.

Although all the various receptor subtypes examined can relieve pain, each receptor represents a different mechanism of action. Their sites of action within the brain differ and, most importantly, agents highly selective for a specific subtype do not show cross-tolerance. While tolerance develops with continued activation of any of the various receptors, tolerance to one does not lead to tolerance to another. For example, tolerance to morphine does not diminish the response to a kappa or delta drug. Similarly, mu agonists produce a characteristic variety of physical dependence, and there is cross-dependence among mu agonists (that is, people dependent on heroin will not experience withdrawal if given methadone.) However, there is no cross-dependence between mu agonists and kappa agonists.

All the various subtypes produce a number of actions other than analgesia. Most of the nonanalgesic actions of opiates can be explained by considering the receptors to which they interact. An excellent example is mu₂ receptors, which mediate respiratory depression and the constipation seen with morphine. Drugs that are agonists at these receptors also produce these side effects while compounds lacking affinity for these receptors do not. The role of multiple receptors is important clinically, primarily since few drugs are specific for one receptor. Even morphine, which is highly selective for mu receptors, interacts with two mu subtypes, and at higher doses with delta receptors as well.

CLASSES OF OPIOIDS

Opioids can be divided into a series of classes based upon their chemical structures, illustrated by prototypic compounds from each group (see Figure 1). These include morphine and its close analogs, the morphinans, the benzomorphans, the phenylpiperidines, and methadone. The pharmacology of agents within each category can be quite varied and often can be predicted from their affinity for various opioid-receptor subtypes. Most of the clinically relevant drugs will interact with more than one receptor. Thus, their actions can be ascribed to the summation of a number of receptor actions.

The importance of various regions of the morphine molecule has been well studied and a number of related compounds are widely used (see Figure 2). Early studies examined small changes in morphine's structure. One of the critical groups is the hydroxyl group at the 3-position on the molecule. Blockade of this position by adding chemical groups markedly reduces the ability of the drug to bind to opioid receptors. Although this may seem at odds with the analgesic activity of codeine, which lacks a free hydroxyl group at the 3-position, evidence indicates that codeine itself is not active and is metabolized to morphine, which is responsible for its actions. A similar situation exists for OXYMORPHONE and OXYCODONE.

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 methylcyclopropyl (-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 nitrogen, 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 analgesics, such as methadone. The phenylpiperidines 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 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 enkephalins—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 β-endorphin, a 31 amino acid peptide derived from a larger protein, which also gives rise to active compounds, including ACTH and α-MSH. The first five amino acids in β-endorphin are identical to [met⁵]enkephalin, but [met]enkephalin and β-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 α-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 10,000-fold more selectively than others. Yet other peptides are very much like morphine in terms of their pharmacology and receptor binding. Finally, peptides 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; )

GAVRIL W. PASTERNAK

REVISED BY REBECCA MARLOW-FERGUSON