title: Naturally occurring clavines: antagonism/partial agonism at 5-HT2A receptors and antagonism at alpha 1-adrenoceptors in blood vessels.
abstract: The interaction of eight typical representatives of naturally occurring clavines (agroclavine, costaclavine, dihydrolysergol-l, elymoclavine, festuclavine, lysergene, lysergol, and pyroclavine) with 5-HT2A receptors and alpha 1-adrenoceptors was studied in rat tail artery and aorta, respectively. Clavines antagonized 5-HT-induced contractions with calculated pKB values (pKP values for partial agonists) of 4.84-7.81 and (R)-phenylephrine-induced contractions with calculated pKB values of 5.34-7.09. Specificity of clavines at 5-HT2A receptors relative to alpha 1-adrenoceptors was rather low. Low affinity for costaclavine at both 5-HT2A receptors (pKP = 4.84 +/- 0.06) and alpha 1-adrenoceptors (pKB = 5.34 +/- 0.05) indicates that the trans-junction of ring C and D of the ergoline pharmacophore is crucial for the binding of ergolines to these sites. Lysergol, lysergene, and costaclavine produced non-parallel displacements of the 5-HT concentration-response curve in the rat tail artery and caused small contractions by themselves. Lysergol contracted the rat tail artery with a pEC50 of 6.36 +/- 0.04 and an intrinsic activity of 0.18 +/- 0.03 with respect to 5-HT. Lysergol-induced contractile responses were surmountably antagonized by ketanserin (10 nM) with a pKB of 9.1 which is consistent with an interaction of lysergol with 5-HT2A receptors. The pKP for the lysergol-5-HT2A receptor complex calculated from concentration-response curves to lysergol was 6.88 +/- 0.07 and did not match the pKP of 7.66 +/- 0.02 calculated from antagonism by lysergol of the contractile response to 5-HT. This suggests that lysergol and 5-HT possibly bind in two slightly different orientations at the 5-HT2A receptor. It is concluded that partial agonism and pure antagonism at 5-HT2A receptors on the one side and antagonism at alpha 1-adrenoceptors on the other side may contribute to the noxious effects of naturally occurring clavines.
authors.affiliation: Institut für Pharmazie II, Pharmazeutische Biologie, Freie Universität Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Pertz
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D004873:Ergolines / Q000494:pharmacology*; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D004873:Ergolines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin