The pharmacological properties of 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methyl-8 beta-aminomethylergoline (LEK-8829) and 9,10-didehydro-N-methyl-N-(2-propynyl)-2-bromo-6-methylergoline -8-beta-carboxamide (LEK-8841), new ergoline derivatives, were compared with those of haloperidol and clozapine by in vitro radioligand displacement assays, various behavioral tests and blood pressure measurements. Both ergolines displayed low affinity for rat striatal 3H-SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pin e)- labeled dopamine (D)1 binding sites and high affinity for striatal 3H-spiperone-labeled D2 and cortical 3H-ketanserin-labeled serotonin-2 (5-HT2) sites. The ratio of pKi values 5-HT2/D2 was 1.11 for LEK-8829 (close to that of clozapine, 1.13) and 0.98 for LEK-8841 (close to that of haloperidol, 0.95). All compounds inhibited apomorphine-induced locomotor activity in rats, apomorphine-induced climbing behavior in mice and 5-hydroxytryptophan-induced head twitches in mice and induced catalepsy in rats and in mice. LEK-8829 and clozapine, but not LEK-8841 and haloperidol, showed a certain degree of mesolimbic selectivity, i.e., they caused more potent inhibition of apomorphine-induced locomotion compared with the induction of catalepsy in rats. In the case of LEK-8829, nonspecific effects that presumably predict a side effect profile, such as potentiation of pentobarbital-induced anesthesia in mice (sedation), antagonism of oxotremorine-induced tremors in mice (anticholinergic activity), spontaneous locomotor activity in mice and norepinephrine-induced lethality in rats (sedation and hypotension), were relatively weak compared with the activities described earlier. In contrast, LEK-8841 showed nonspecific effects at the similar dose levels as dopamine and 5-HT antagonistic effects. The results of direct measurements of the influences of both compounds on blood pressure agreed with the previously mentioned findings, i.e., LEK-8829 was relatively less hypotensive than LEK-8841 was. It is suggested that LEK-8829 might be an efficient antipsychotic with a reduced propensity to cause sedative, anticholinergic and hypotensive side effects. A certain degree of mesolimbic selectivity also points toward the possibility of a reduced propensity to cause extrapyramidal symptoms. In contrast, in regard to side effects (including extrapyramidal symptoms), the profile of LEK-8841 is less promising.

1992-01-01·Pharmacology4区 · 医学

Structure-Activity Study of Some Newly Synthesized Ergoline Derivatives on 5-HT<sub>2</sub> Receptors and Alpha-Adrenoceptors in Rabbit Isolated Aorta

4区 · 医学

Article

作者: Krisch, Igor ; Budihna, Metka V. ; Rucman, Rudolf

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.

100 项与 LEK-841 相关的药物交易

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