Naturally occurring clavines: Antagonism partial agonism at 5-HT2A receptors and antagonism at alpha(1)-adrenoceptors in blood vessels

The interaction of eight typical representatives of naturally occurring clavines (agroclavine, costaclavine, dihydrolysergol-1, 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 pK(B) values (pK(P) values for partial agonists) of 4.84-7.81 and (R)-phenylephrine-induced contractions with calculated pK(B) values of 5.34-7.09. Specificity of clavines at 5-HT2A receptors relative to alpha(1)-adrenoceptors was rather low. tow affinity for costaclavine at both 5-HT2A receptors (pK(P) = 4.84 +/- 0.06) and alpha(1)-adrenoceptors (pK(B) = 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, acid 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 pEC(50) 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 pK(B) of 9.1 which is consistent with an interaction of lysergol with 5-HT2A receptors. The pK(P) for the lysergol-5-HT2A receptor complex calculated from concentration-response curves to lysergol was 6.88 +/- 0.07 and did not match the pK(P) 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.