Synthesis and Anticonvulsant Activity of Novel and Potent 6,7-Methylenedioxyphthalazin-1(2H)-ones

• Published in: Journal of medicinal chemistry Vol. 43; no. 15; pp. 2851 - 2859
• Main Authors: Grasso, Silvana, De Sarro, Giovambattista, De Sarro, Angela, Micale, Nicola, Zappalà, Maria, Puja, Giulia, Baraldi, Mario, De Micheli, Carlo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.07.2000; Amer Chemical Soc
• Subjects: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Cells, Cultured; Chemistry, Medicinal; Convulsants; Drug Evaluation, Preclinical; Electroshock; Excitatory Amino Acid Agonists; Isoxazoles; Kainic Acid; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Inbred DBA; Neurons - drug effects; Neurons - physiology; Neuropharmacology; Patch-Clamp Techniques; Pentylenetetrazole; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phthalazines - chemical synthesis; Phthalazines - chemistry; Phthalazines - pharmacology; Propionates; Receptors, AMPA - agonists; Receptors, Kainic Acid - agonists; Science & Technology; Seizures - drug therapy; Seizures - etiology; Structure-Activity Relationship; AMPA RECEPTOR ANTAGONISTS; KAINATE; RESPONSES; GYKI 52466; 2,3-BENZODIAZEPINES; AMINO-ACIDS; NMDA; DBA/2 MICE; HIPPOCAMPAL-NEURONS; GYKI-52466; Nervous system diseases; Intraperitoneal administration; Rodentia; Benzene derivatives; Anticonvulsant; Tricyclic compound; Audiogenic epilepsy; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Convulsion; Structure activity relation; Mouse; Animal; Central nervous system disease; Aromatic compound; Neurological disorder; Chemical synthesis; Oxygen nitrogen heterocycle; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm001002x

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 μmol/kg for 21 versus ED50 35.8 μmol/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-butylisoxazol-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-methylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.