title: Synthesis and evaluation of pharmacological and pharmacokinetic properties of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones.
abstract: 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.
authors: Dipartimento Farmaco-Chimico and Istituto di Farmacologia, Facoltà di Medicina e Chirurgia, Università di Messina, Messina, Italy.
authors: M
authors: M
authors: Zappalà
authors: R
authors: R
authors: Gitto
authors: F
authors: F
authors: Bevacqua
authors: S
authors: S
authors: Quartarone
authors: A
authors: A
authors: Chimirri
authors: M
authors: M
authors: Rizzo
authors: G
authors: G
authors: De Sarro
authors: A
authors: A
authors: De Sarro
mesh_terms: D000161:Acoustic Stimulation; D000494:Allosteric Regulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D011760:Pyrrolidinones / Q000627:therapeutic use; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D018091:Receptors, AMPA; D001569:Benzodiazepines; C036466:aniracetam; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D010433:Pentylenetetrazole