Abstract
The interaction of eight typical representatives of naturally occurring clavines (agroclavine,
costaclavine, dihydrolysergol-I, elymoclavine, festuclavine, lysergene, lysergol,
and pyroclavine) with 5-HT2A receptors and α1-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 α1 adrenoceptors was rather low. Low affinity for costaclavine at both 5-HT2A receptors (pKP = 4.84 ± 0.06) and α1-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 α1-adrenoceptors on the other side may contribute to the noxious effects of naturally
occurring clavines.
Key words
Naturally occurring clavines - 5-HT2A receptors - α1-adrenoceptors - partial agonism - antagonism
