Naturally Occurring Clavines: Antagonism/Partial Agonism at 5-HT_2A Receptors and Antagonism at α₁-Adrenoceptors in Blood Vessels

Abstract

The interaction of eight typical representatives of naturally occurring clavines (agroclavine, costaclavine, dihydrolysergol-I, elymoclavine, festuclavine, lysergene, lysergol, and pyroclavine) with 5-HT_2A receptors and α₁-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-HT_2A receptors relative to α₁ adrenoceptors was rather low. Low affinity for costaclavine at both 5-HT_2A receptors (pK_P = 4.84 ± 0.06) and α₁-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, 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 pK_B of 9.1 which is consistent with an interaction of lysergol with 5-HT_2A receptors. The pK_P for the lysergol-5-HT_2A 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-HT_2A receptor. It is concluded that partial agonism and pure antagonism at 5-HT_2A receptors on the one side and antagonism at α₁-adrenoceptors on the other side may contribute to the noxious effects of naturally occurring clavines.

Key words

Naturally occurring clavines - 5-HT_2A receptors - α₁-adrenoceptors - partial agonism - antagonism