Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of 11H-[1,2,4]Triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones

• Published in: Journal of medicinal chemistry Vol. 43; no. 25; pp. 4834 - 4839
• Main Authors: Zappalà, Maria, Gitto, Rosaria, Bevacqua, Francesca, Quartarone, Silvana, Chimirri, Alba, Rizzo, Milena, De Sarro, Giovambattista, De Sarro, Angela
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2000; Amer Chemical Soc
• Subjects: Acoustic Stimulation; Allosteric Regulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacokinetics; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacokinetics; Benzodiazepines - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Chromatography, High Pressure Liquid; Electroshock; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacokinetics; Excitatory Amino Acid Antagonists - pharmacology; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Mice, Inbred DBA; Motor Activity - drug effects; Neuropharmacology; Pentylenetetrazole; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrrolidinones - therapeutic use; Receptors, AMPA - antagonists & inhibitors; Science & Technology; Seizures - drug therapy; Seizures - etiology; Structure-Activity Relationship; AMPA RECEPTOR ANTAGONISTS; HIGH-PERFORMANCE LIQUID; GLUTAMATE RECEPTORS; 2,3-BENZODIAZEPINES; CHANNEL; ANTICONVULSANT ACTIVITY; EPILEPSY-PRONE RATS; DBA/2 MICE; CHROMATOGRAPHY; PLASMA-LEVEL; Intraperitoneal administration; Rat; Angular nitrogen heterocycle; Anticonvulsant; Glutamate receptor; Structure activity relation; Aromatic compound; Antagonist; Diether; Chemical synthesis; Nervous system diseases; Rodentia; Benzene derivatives; Tricyclic compound; Cerebral disorder; Audiogenic epilepsy; Vertebrata; Chemotherapy; Experimental disease; AMPA receptor; Mammalia; Treatment; Convulsion; Mouse; Animal; Central nervous system disease; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm001012y

A series of 2,3-benzodiazepine derivatives has been previously described as noncompetitive AMPA-type glutamate receptor antagonists potentially useful for treatment of epilepsy. To further explore the structure−activity relationships of AMPA antagonists, a series of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) was synthesized starting from the corresponding bicyclic 1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. In addition, they antagonize the AMPA-induced seizures, and their anticonvulsant activity is reversed by pretreatment with aniracetam, thus suggesting the involvement of AMPA receptors. The pharmacological studies revealed that the 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) herein reported show anticonvulsant activity comparable to that of their bicyclic precursors. Furthermore, an HPLC study put in evidence that these tricyclic derivatives 6 were converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.