1 CHO-K1 cells that were stably transfected with the gene for the human AT 1 receptor (CHO-AT 1 cells) were used for pharmacological studies of non-peptide AT 1 receptor antagonists. 2 In the presence of 10 mM LiCl, angiotensin II caused a concentration-dependent and long-lasting increase of inositol phosphates accumulation with an EC 50 of 3.4 nM. No angiotensin II responses are seen in wild-type CHO-K1 cells. 5 Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory e ects were halfmaximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 mM losartan indicating a syntopic action of both antagonists. 6 Losartan caused a parallel rightward shift of the angiotensin II concentration-response curves and did not a ect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed-type behavior in both functional and binding studies. 7 Reversal of the inhibitory e ect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT 1 receptor antagonists in functional studies was related to their long-lasting inhibition.
The fruit and the leaves of Annona muricata (Annonaceae) are used in traditional medicine for their tranquillizing and sedative properties. Extracts of the plant have been shown to inhibit binding of [3H]rauwolscine to 5-HTergic 5-HT1A receptors in calf hippocampus, and three alkaloids, annonaine (1), nornuciferine (2) and asimilobine (3), isolated from the fruit have been shown to have IC50 values of 3 microM, 9 microM and 5 microM, respectively, although in ligand-binding studies it was not possible to determine whether interaction of these ligands with the receptor was agonistic or antagonistic. This paper presents the results of functional assays of the alkaloids. The inhibition of cAMP accumulation was tested in NIH-3T3 cells stably transfected with the 5-HT1A receptor from man. None of the alkaloids showed antagonistic properties towards the 5-HT1A receptors because in the antagonistic tests no influence on the forskolin-stimulated increase of cAMP level was detected. Full agonistic properties were measured for all three compounds; the inhibition constants (Ki) for 1, 2 and 3 were < 10 microM. Inhibition of the binding of the radioligand to the 5-HT1A receptor was observed in every ligand-binding assay performed with the alkaloids; the Ki values for 1, 2 and 3 were in the microM range. These results imply that the fruit of Annona muricata possesses anti-depressive effects, possibly induced by compounds 1, 2 and 3, and that in the past potent leads for the development of anti-depressive therapeutics have not been used.
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