Structure-Activity Study of Some Newly Synthesized Ergoline Derivatives on 5-HT₂ Receptors and Alpha-Adrenoceptors in Rabbit Isolated Aorta

Abstract

In a structure-activity study, carried out in rabbit isolated aorta, the effect of different structural modifications in the ergoline nucleus upon the activity at 5-HT₂ receptors and α-adrenoceptors was determined. 9,10-didehydro – N- methyl – N- (2-propynyl) – 6 – methylergoline – 8 β-carboxamide (LEK 8842) was chosen as the basic backbone of this study. The parent compound LEK 8842 showed strong α-adrenoceptor agonistic activity and partial 5-HT₂ receptor agonistic activity, and its potency (pD₂ = 6.41) was comparable with that of 5-hydroxytryptamine (5-HT, pD₂ = 6.84) and noradrenaline (pD₂ = 6.82). Hydrogenation of the double bond in the position 9,10 (LEK 8822) attenuated the potency (pD₂ = 5.35) as well as the intrinsic activity on α-adrenoceptors and eliminated 5-HT₂ receptor agonistic activity. LEK 8822 acted on the α-adrenoceptors not only as a partial agonist but also as a competitive antagonist of responses elicited by noradrenaline. When tested against 5-HT, LEK 8822 acted as an antagonist. Bromination in position 2 yielded the derivative LEK 8841 with no agonistic activity at concentrations up to 3 μmol/l, yet the affinity for 5-HT₂ receptors and α-adrenoceptors was preserved. LEK 8841 was the only one that acted as pure simple competitive antagonist of responses elicited by 5-HT (pA₂ = 7.93) and noradrenaline (pA₂ = 6.45). Its activity was qualitatively similar to that observed with the 5-HT₂/α-adrenoceptor antagonist ketanserin which was tested for comparison. Concerning selectivity for 5-HT₂ receptors versus α-adrenoceptors, LEK 8841 proved to be more selective for 5-HT₂ receptors than ketanserin. pA₂ values for ketanserin antagonistic activity to 5-HT and to noradrenaline were 8.22 and 7.48, respectively. Finally, quaternization in the N(6) position (LEK 8827) almost completely eliminated affinity for 5-HT₂ receptors and for α-adrenoceptors. This study has shown that relatively small modifications in the structure of the ergoline system led to pronounced changes in the affinity as well as intrinsic activity at both receptors studied.

Does serotonin relax the rat anococcygeus muscle via 5-HT 7 receptors?

“…However, none of the antagonists except ketanserin affected the concentration-response curve to 5-HT. Although ketanserin, a classical 5-HT 2A receptor antagonist, inhibited the contractions, the involvement of 5-HT 2A type receptors in the response to 5-HT could not be suggested, because ketanserin is known to block α 1 -adrenoceptors, as well (Krisch et al 1992). Furthermore methysergide, a 5-HT 1 and 5-HT 2 receptor antagonist, and ritanserin, a more selective antagonist for 5-HT 2A type receptors, did not change the responses to 5-HT.…”

A New Ergoline Derivative, LEK‐8829, as a Potential New Antipsychotic Drug

“…LEK-8829 behaved only as a weak competitive antagonist of contractile responses elicited by noradrenaline (pA2 6.1 1, slope 0.96) (15). In this model, serotonin and noradrenaline elicit contractions via stimulation of 5-HTzA and a,-adrenoceptors, respectively (2,16). Under similar experimental conditions, LEK-8829 (0.1 pmol/L) caused minimal constriction of the rabbit inferior vena cava (about 10% of maximal noradrenaline effect).…”

Dopamine Agonists in the Treatment of Parkinsons Disease-Past, Present and Future

“…References specifically directed to SAR elucidation and pharmacology have appeared [73][74][75][76][77][78][79][80][81][82][83][84].…”