Isoquinoline Derivatives Isolated from the Fruit of Annona muricata as 5-HTergic 5-HT1A Receptor Agonists in Rats: Unexploited Antidepressive (Lead) Products

Abstract

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.

5-Hydroxytryptamine1Areceptor binding activity of bisbenzyltetrahydroisoquinoline alkaloids fromPopowia odoardi

“…This is higher than the inhibition constants of (±)-8-hydroxy-2-(di-npropylamino)-tetralin [(±)-8-OH-DPAT] buspirone, and 5-hydroxytryptamine (5-HT) ( Table 1). The values are several-fold higher than that of propanolol (0.14 M), a 5HT 1A /5HT 2 receptor antagonist, but are similar to those of other structurally related isoquinoline alkaloids, such as annonaine, nornuciferine and asimilobine (less than 10 M) (Figure 4) (Hasrat et al, 1997a).…”

“…The IC 50 values for inhibition of receptor binding for annonaine, nornuciferine, and asimilobine were 3, 9, and 5 M, respectively (Hasrat et al, 1997b), which are close to the K i values of O-methyldauricine (1) (4.5 M) and popisidine (2) (5.8 M). In the functional assay, based on the inhibition of the accumulation of cAMP in NIH-3T3 cells stably transfected with 5-HT 1A receptor from human, the K i values for annonaine, nornuciferine, and asimilobine were estimated to be less than 10 M (Hasrat et al, 1997a). In another study, the IC 50 for the interaction of annonaine with the dopamine reuptake pump was reported to be 0.8 M (Protais et al, 1995).…”

Synthesis of Isoquinolinones via Regioselective Palladium-Catalyzed C–H Activation/Annulation

“…Selected results for the optimization of the reaction conditions for oxidative annulation. 1 Catalysts 2017, 7, 320 3 of 9 which used [{RhCp*Cl2}2] as catalyst and CsOAc as additive. However, no desired product was observed when the reaction was performed in methanol at room temperature.…”

“…Isoquinoline and its derivatives form the cores of numerous natural products and they are the central components of many pharmaceutical agents [1][2][3][4]. Due to their unique DNA binding properties, isoquinolines and their derivatives show a wide range of biological activities, such as in vasodilatation [5][6][7], as well as for its antibacterial [3,8,9], anti-malarial [10], anti-HIV [11,12] and anti-tumor properties [13][14][15].…”

In vitro and in vivo evaluation of antitrypanosomal activity of Annona muricata stem bark extracts.

“…All parts of the plant are used in natural medicine in the tropics [6][7][8]. Some of its uses in natural medicine such as hypotensive, antispasmodic, anticonvulsant, vasodilator and smooth muscle relaxant activities have been validated by scientific research in animal studies [6,9,10].…”