Abstract

The interactions of ergot alkaloids with bovine anterior pituitary D-2 dopamine receptors have been investigated with radioligand binding techniques and computer modeling procedures. Ergot alkaloids of the ergoline class are found to interact with the receptor in an agonist-specific fashion, exhibiting heterogeneous competition curves which can be resolved into high- and low-affinity components. In the presence of guanine nucleotides, however, only the low-affinity binding component is observable. In contrast, ergot alkaloids possessing a cyclic peptide side chain (ergopeptines) interact with the receptor in a homogeneous fashion, exhibiting competition curves which are monophasic and unaffected by guanine nucleotides. Ergopeptines thus display the binding characteristics of antagonist ligands even though they possess pharmacologically demonstrated agonist properties. These ergot alkaloid receptor binding characteristics determined from indirect competition experiments are also directly demonstrable using radiolabeled ergoline and ergopeptine ligands. The radiolabeled ergopeptine [3H]dihydroergocryptine ([3H]DHE) is shown to label identical binding sites with the same pharmacological characteristics as the antagonist [3H]spiroperidol. However, the dissociation rate of [3H]DHE from these binding sites is much slower than [3H]spiroperidol and is inconsistent with its equilibrium-determined binding affinity. In addition, saturation experiments with radiolabeled antagonists and agonists and unlabeled ergopeptines indicate that ergopeptines interact with these receptor sites in a competitive fashion. A model is presented which may explain these unique binding properties of ergot alkaloid agonists to the pituitary D-2 dopamine receptor.