Structure-activity study of some newly synthesized ergoline derivatives on 5-HT2 receptors and alpha-adrenoceptors in rabbit isolated aorta.

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 alpha-adrenoceptors was determined. 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methylergoline-8 beta-carboxamide (LEK 8842) was chosen as the basic backbone of this study. The parent compound LEK 8842 showed strong alpha-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 alpha-adrenoceptors and eliminated 5-HT2 receptor agonistic activity. LEK 8822 acted on the alpha-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 mumol/l, yet the affinity for 5-HT2 receptors and alpha-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/alpha-adrenoceptor antagonist ketanserin which was tested for comparison. Concerning selectivity for 5-HT2 receptors versus alpha-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 alpha-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.