The ergot alkaloids act on several types of receptors. As shown by the color outlines in Table 16–7, the nuclei of both catecholamines (phenylethylamine, left panel) and 5-HT (indolethylamine, right panel) can be discerned in the ergoline nucleus. Their effects include agonist, partial agonist, and antagonist actions at α adrenoceptors and serotonin receptors (especially 5-HT1A and 5-HT1D; less for 5-HT2 and 5-HT3); and agonist or partial agonist actions at central nervous system dopamine receptors (Table 16–8). Furthermore, some members of the ergot family have a high affinity for presynaptic receptors, whereas others are more selective for postjunctional receptors. There is a powerful stimulant effect on the uterus that seems to be most closely associated with agonist or partial agonist effects at 5-HT2 receptors. Structural variations increase the selectivity of certain members of the family for specific receptor types.
TABLE 16–8 Effects of ergot alkaloids at several receptors.1 1Agonist effects are indicated by +, antagonist by −, no effect by 0. Relative affinity for the receptor is indicated by the number of + or − signs. PA means partial agonist (both agonist and antagonist effects can be detected).
B. Organ System Effects 1.
Central nervous system—As indicated by traditional descriptions of ergotism, certain of the naturally occurring alkaloids are powerful hallucinogens. Lysergic acid diethylamide (LSD; “acid”) is a synthetic ergot compound that clearly demonstrates this action. The drug has been used in the laboratory as a potent peripheral 5-HT2 antagonist, but good evidence suggests that its behavioral effects are mediated by agonist effects at prejunctional or postjunctional 5-HT2 receptors in the central nervous system. In spite of extensive research, no clinical value has been discovered for LSD’s dramatic central nervous system effects. Abuse of this drug has waxed and waned but is still widespread. It is discussed in Chapter 32.
Dopamine receptors in the central nervous system play important roles in extrapyramidal motor control and the regulation of pituitary prolactin release. The actions of the peptide ergoline bromocriptine on the extrapyramidal system are discussed in Chapter 28. Of all the currently available ergot derivatives, bromocriptine, cabergoline, and pergolide have the highest selectivity for the pituitary dopamine receptors. These drugs directly suppress prolactin secretion from pituitary cells by activating regulatory dopamine receptors (see Chapter 37). They compete for binding to these sites with dopamine itself and with other dopamine agonists such as apomorphine. They bind with high affinity and dissociate slowly.
2.
Vascular smooth muscle—The actions of ergot alkaloids on vascular smooth muscle are drug-, species-, and vessel-dependent, so few generalizations are possible. In humans, ergotamine and similar compounds constrict most vessels in nanomolar concentrations (Figure 16–4). The vasospasm is prolonged. This response is partially blocked by conventional α-blocking agents. However, ergotamine’s effect is also associated with “epinephrine reversal” (see Chapter 10) and with blockade of the response to other α agonists. This dual effect reflects the drug’s partial agonist
Percent of maximum 5-HT contraction action (Table 16–7). Because ergotamine dissociates very slowly from the α receptor, it produces very long-lasting agonist and antagonist effects at this receptor. There is little or no effect at β adrenoceptors.