Dopaminergic activity of some ergot alkaloid derivatives: relationship to their chemical structure.
Several ergot alkaloid derivatives have been tested for their ability to inhibit receptor binding of [3H]spiperone (D2 dopamine receptors) and [3H]dopamine (D3 dopamine receptors) in the bovine caudate nucleus. Dopaminergic activity was correlated to their chemical structure. The potencies of ergot alkaloids for displacing [3H]spiperone binding can be ranked in the following order: lisuride greater than ergosine greater than bromodihydroergosine greater than bromoergosine approximately dihydroergosine approximately ergosinine approximately dihydroergocryptine greater than bromoergocryptine greater than CH-29 717 greater than saccharinoergosinine = saccharinoergosine greater than dihydroergosinine. The potencies of these compounds for displacing [3H]dopamine binding can be ranked in the following order: lisuride greater than ergosinine approximately ergosine greater than dihydroergosine greater than bromodihydroergosine approximately CH-29 717 approximately bromoergocryptine approximately bromoergosine approximately dihydroergocryptine greater than saccharinoergosine, saccharinoergosinine, dihydroergosinine. Displacement of both radioligands was unaffected by GTP. Binding characteristics of ergot alkaloids examined revealed antagonist-like properties of binding to D2 and agonist-like properties of binding to D3 receptors. Introduction of bromine into position 2, selective hydrogenation of 9,10-dihydroderivatives, or isomerization in position 8 of the ergot alkaloid molecule did not drastically change binding parameters of these compounds. However, an alpha-configuration in position 8 combined with hydrogenation of the delta-9,10-double bond of dihydroergosinine, significantly decreased its affinity to both D2 and D3 receptors in comparison with dihydroergosine or ergosinine, suggesting stereoselectivity of dopamine receptors towards the pair dihydroergosine/dihydroergosinine.
D000818:Animals; D002417:Cattle; D002421:Caudate Nucleus / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004873:Ergolines / Q000494:pharmacology; D004876:Ergot Alkaloids / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D008968:Molecular Conformation; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
D004873:Ergolines; D004876:Ergot Alkaloids; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D014316:Tritium; D013134:Spiperone; D006160:Guanosine Triphosphate; D004298:Dopamine