Cycloalkanecarboxylic esters derived from lysergol, dihydrolysergol-I, and elymoclavine as partial agonists and antagonists at rat 5-HT(2A) receptors: Pharmacological evidence that the indolo[4,3-fg]quinoline system of the ergolines is responsible for high 5-HT(2A) receptor affinity

Article abstract of DOI:10.1021/jm981092u

Three series of cycloalkanecarboxylic esters derived from the naturally occurring clavine alkaloids lysergol, dihydrolysergol-I, and elymoclavine were synthesized to study their interaction with 5-HT(2A) receptors and α₁- adrenoceptors in rat tail artery and aorta, respectively. Especially cycloalkanecarboxylic esters derived from lysergol showed complex behavior as partial agonists and antagonists of the contractile effect of 5-HT. Within this group, partial 5-HT(2A) receptor agonist activity was most potent for cyclopropanecarboxylic ester 6a (pK(p) = 7.67, α = 0.21) and decreased as the volume requirement of the alicyclic ring increased. This tendency was echoed in experiments where the compounds were used as antagonists of the contractile effect of 5-HT. From the structure-activity study, the N-1- isopropyl homologue of 6a, compound 6b, emerged as the ligand with the highest affinity for rat 5-HT(2A) receptors (pA₂ = 8.74). For cycloalkanecarboxylic esters derived from dihydrolysergol-I and elymoclavine, no clear structure-affinity relationship could be deduced, although those compounds that had smaller cycloalkyl rings in the acyl portion and an isopropyl substituent at N-1 showed the highest 5-HT(2A) receptor affinity. On the other hand, cycloalkanecarboxylic esters derived from lysergol, dihydrolysergol-I, and elymoclavine displayed low or marginal affinity at α₁-adrenoceptors. A further aim of the study was to examine to what extent the complete removal of the acyl portion of the esters would affect 5-HT(2A) receptor affinity. The parent alcohols of the three series of N-1-isopropyl homologues, 1-isopropyllysergol (1b), 1-isopropyldihydrolysergol-I (2b), and 1-isopropylelymoclavine (3b), displayed higher affinity for 5-HT(2A) receptors (pA₂ = 9.15, 8.50, 9.14) than the corresponding esters. Compounds 1b-3b had no contractile effects by themselves and displayed low affinity at guinea-pig 5-HT(1B) receptors and rat α₁-adrenoceptors. The high affinity for rat 5-HT(2A) receptors was retained when clavines even more simple in structure than 1b-3b, compounds 4b and 5b, were examined as 5-HT(2A) receptor antagonists. The nanomolar antagonist activity of simple clavines (1b-5b) in the rat suggests that the indolo-[4,3-fg]quinoline system of the ergolines is the molecular fragment that is responsible for 5-HT(2A) receptor affinity, and not the substituent at position C-8.