O-Acylated lysergol and dihydrolysergol-I derivatives as competitive antagonists of 5-HT at 5-HT2 receptors of rat tail artery

1432-1912

5-HT2 receptors ; Lysergol and dihydrolysergol-I derivatives ; Methysergide ; LY 53857 ; Allosteric modulation

Springer Online Journal Archives 1860-2000

Medicine

Summary Twelve ergolines (O-Ayated lysergol and dihydrolysergol-I derivatives) were synthesized to study their antagonism of 5-HT responses in comparison with methysergide and LY 53857 [6-methyl-l-(1-methylethyl)-8β-ergoline carboxylic acid 2-hydroxy-l-methyl-propylester hydrogen maleate] in cylindrical segments of the isolated rat tail artery. With regard to (9.10-didehydro-6-methyl-8β-ergoline)methyl R,S-2-methylbutyrate, the most potent new ergoline derivative, we examined the phenomenon of insurmountable antagonism to 5-HT by methysergide. O-Acylated lysergol and dihydrolysergol-I derivatives competitively antagonized 5-HT-induced contractions with calculated pA2. values of 7.30 ± 0.42 for the weakest and 8.42 ± 0.35 for the most potent ergoline derivative in this series. N1-isopropyl substitution did not generally enhance 5-HT2 receptor affinities but lowered affinities for α1 adrenoceptors in rat aorta. Methysergide and LY 53857 were insurmountable, antagonists of 5-HT in rat tail artery. Preincubation with (9.10-didehydro-6-methyl-8β-ergoline)methyl R,S-2-methylbutyrate (1 μmol/l) partially prevented the depression of 5-HT-induced contractions caused by methysergide (1–10 nmol/l). Methysergide (100 nmol/l) abolished the protective effect of (9.10-didehydro-6-methyl-8β-ergoline)methyl R,S-2-methylbutyrate. (9.10-Didehydro-6-methyl-8β-ergoline)methyl R,S-2-methylbutyrate (1 μmol/l), concomitantly incubated with methysergide (30 nmol/l), partially restored the maximum response to 5-HT that had been depressed by methysergide (30 nmol/l). Partial restoration could not be mimicked by washout of methysergide. In view of this result, it is suggested that insurmountable antagonism by methysergide of 5-HT responses in rat tail artery is due to allosteric modulation of 5-HT2 receptors rather than pseudoirreversible inhibition.

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