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In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.

Extracts from pods and leaves of carob (Ceratonia siliqua L.) were tested for their ability to inhibit cell proliferation of mouse hepatocellular carcinoma cell line (T1). The two extracts showed a marked alteration of T1 cell proliferation in a dose-related fashion reaching the maximal effect at 1 mg/ml. Moreover, we demonstrated that leaf and pod extracts were able to induce apoptosis in T1 cell lines after 24-h treatment mediating a direct activation of the caspase 3 pathway. HPLC analysis revealed the presence of gallic acid, (-) epigallocatechin-3-gallate and (-) epicatechin-3-gallate in pod and leaf extracts, compounds well known to exert antiproliferative effects. Their concentration reached 6.28 mg/g in carob leaves and 1.36 mg/g in carob pods extract. The discovery that carob pod and leaf extracts contained antiproliferative agents could be of practical importance in the development of functional foods and/or chemopreventive drugs.

Immunoreactive (Ir) beta-endorphin concentrations were determined in plasma, anterior pituitary (AP), neurointermediate pituitary lobe (NIL) and mediobasal hypothalamus (MBH) of pregnant (12-14 and 18-20 days) and fertile control rats, during labour and lactation. Immunoreactive Met-enkephalin concentrations were also evaluated in the MBH. Concentrations of Ir beta-endorphin in plasma, AP and NIL of rats during early and late pregnancy were significantly higher than in controls, the plasma and AP contents showing an increasing pattern in the second half of gestation. During labour, Ir beta-endorphin concentrations in plasma and AP reached the highest values, whereas those in NIl remained unchanged. Lactating rats showed Ir beta-endorphin concentrations in NIL and plasma in a range similar to that found in pregnant rats, resulting in concentrations in the AP not significantly different from those of nonpregnant controls. Immunoreactive beta-endorphin and Ir Met-enkephalin concentrations in MBH of pregnant rats were almost twice as high as in controls, rising markedly during labour; during lactation levels were in the same range as in non-pregnant controls. These results indicate that pregnancy and labour are characterized by high plasma, pituitary and hypothalamic concentrations of Ir-beta-endorphin as well as by high hypothalamic Ir Met-enkephalin levels, and that Ir beta-endorphin concentrations vary differently during pregnancy, lactation and labour in the two pituitary lobes, supporting the existence of different control mechanisms in the AP and NIL.

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