Oh

-h

-GH2—0

"-0H group added to position 14. "Oxygen bridge missing.

""■*Etheno bridge inserted between positions 6 and 14 rings, plus hydroxy, trim ethyl propyl substitution on position 7.

"-0H group added to position 14. "Oxygen bridge missing.

""■*Etheno bridge inserted between positions 6 and 14 rings, plus hydroxy, trim ethyl propyl substitution on position 7.

Figure 15.2. Structures of opiate analgesics and their antagonists (last five listed).

matter. The importance of receptors in these regions was evaluated by applying morphine to these sites using microinjection. Injection of morphine into the periaqueductal grey matter was found to be associated with analgesia, while retrograde amnesia resulted when the drug was applied to the amygdala, and hyperactivity when injected into the basal ganglia. The high density of opioid receptors in the spinal cord, particularly the substantia gelatinosa, which is an area that is highly innervated by peripheral type C fibres, accounts for the spinal analgesia which many opiates possess.

Actions of opioids on opioid receptors

The first endogenous ligands for the opioid receptors were isolated by Kosterlitz and Hughes and were found to be the pentapeptides methionine and leucine enkephalin (meta- and leu-enkephalin). The structures of these,

FUNDAMENTALS OF PSYCHOPHARMACOLOGY Table 15.3. Structures of some opioid peptides

Leucine enkephalin Tyr-Gly-Gly-Phe-Leu-OH

Methionine enkepahlin Tyr-Gly-Gly-Phe-Met-OH

Gamma-endorphin

Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gin-Thr-Pro-Leu-Val-Thr-Leu-Phe Alpha-endorphin

Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gin-Thr-Pro-Leu-Val-Thr Beta-endorphin

Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gin-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu-OH

and related peptides which also act as endogenous ligands for these receptors, are shown in Table 15.3.

Two further families of opioid peptides have since been isolated, namely the endorphins and the dynorphins. Each family of peptides is derived from a distinct precursor polypeptide, which has been identified as pro-enkephalin (from which both met- and leu-enkephalin are derived), pro-opiomelanocortin (which gives rise to alpha and gamma melanocyte-stimulating hormone (MSH), adrenocorticotrophin hormone (ACTH), beta-lipotropin and met-enkephalin) and pro-dynorphin, which produces alpha-and beta-neoendorphins and leu-enkephalin. Detailed binding studies in the brain and peripheral tissues have now established that these various opioids interact with different categories of receptors, which have been designated mu, kappa and delta receptors. The synthetic opioid compound N-allylnormetazocine (SKF 10047) has been shown to bind preferentially to another class of receptor, termed the sigma receptor, but it is now recognized that this category of opioid receptor is not directly associated with the pharmacological activity of the opioid analgesics.

In addition to the opioid peptides which occur in the mammalian brain, it is now evident that morphine, codeine and related benzomorphans occur naturally, in trace amounts, in the brain, where they exist in a conjugated form usually bound to brain proteins. The significance of these substances to brain function is unclear.

All opioids produce their effect by activating one or more of the three types of receptors. Thus analgesia involves the activation of the mu receptors that are located mainly at supraspinal sites and kappa receptors in the spinal cord; delta receptors may also be involved but their relative contribution is unclear. Nevertheless, the actions of the opioids on these receptors is complex, as there is evidence that the same substance may act as a full agonist, or as an antagonist at different sites within the brain.

Table 15.4. Effects of some opiate agonists and antagonists on opioid receptors in mammalian brain

Opiate agonist or antagonist Receptor type

Opiate agonist or antagonist Receptor type

Table 15.4. Effects of some opiate agonists and antagonists on opioid receptors in mammalian brain

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