ISOQUINOLINE DERIVATIVES ISOLATED FROM THE FRUIT OF ANNONA-MURICATA AS 5-HTERGIC 5-HT1A RECEPTOR AGONISTS IN RATS - UNEXPLOITED ANTIDEPRESSIVE (LEAD) PRODUCTS

The fruit and the leaves of Annona muricata (Annonaceae) are used in t raditional medicine for their tranquillizing and sedative properties. Extracts of the plant have been shown to inhibit binding of [H-3]rauwo lscine to 5-HTergic 5-HT1A receptors in calf hippocampus, and three al kaloids, annonaine (1), nornuciferine (2) and asimilobine (3), isolate d from the fruit have been shown to have IC50 values of 3 mu M, 9 mu M and 5 mu M, respectively, although in ligand-binding studies it was n ot possible to determine whether interaction of these ligands with the receptor was agonistic or antagonistic. This paper presents the resul ts of functional assays of the alkaloids. The inhibition of cAMP accum ulation was tested in NIH-3T3 cells stably transfected with the 5-HT1A receptor from man. None of the alkaloids showed antagonistic properti es towards the 5-HT1A receptors because in the antagonistic tests no i nfluence on the forskolin-stimulated increase of cAMP level was detect ed. Full agonistic properties were measured for all three compounds; t he inhibition constants (K-i) for 1, 2 and 3 were < 10 mu M. Inhibitio n of the binding of the radioligand to the 5-HT1A receptor was observe d in every ligand-binding assay performed with the alkaloids; the K-i values for 1, 2 and 3 were in the mu M range. These results imply that the fruit of Annona muricata possesses anti-depressive effects, possi bly induced by compounds 1, 2 and 3, and that in the past potent leads for the development of anti-depressive therapeutics have not been use d.