3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones:  A New Class of AMPA Receptor Antagonists

Abstract

Synthesis and evaluation of anticonvulsant activity of a series of 2,3-benzodiazepin-4-ones (2) chemically related to 1-(4'-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466) have been reported in our recent publications. Compounds 2 manifested marked anticonvulsant properties acting as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. In an attempt to better define the structure-activity relationships (SAR) and to obtain more potent and selective anticonvulsant agents, 1-aryl-3,5-dihydro-4H-2, 3-benzodiazepine-4-thiones 3 were synthesized from the corresponding isosteres 2. The evaluation is reported of their anticonvulsant effects, both in the audiogenic seizures test with DBA/2 mice and against the maximal electroshock- and pentylenetetrazole-induced seizures in Swiss mice. New derivatives 3 showed higher potency, less toxicity and longer-lasting anticonvulsant action than those of the parent compounds 2 in all tests employed. Analogous to derivatives 2, new compounds 3 do not affect the benzodiazepine receptor (BZR) while they do antagonize AMPA-induced seizures; their anticonvulsant activity is reversed by pretreatment with aniracetam but not with flumazenil, thus suggesting a clear involvement of AMPA receptors. Electrophysiological data indicate a noncompetitive blocking mechanism at the AMPA receptor sites for 3i, the most active of the series and over 5-fold more potent than 1.

The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

“…Hundreds of 3-N-substituted-3,4-dihydro-2,3-benzodiazepine analogues have been developed using talampanel as the lead structure, and some have demonstrated good in vitro AMPA receptor affinity with in vivo efficacy as anti-epileptic drugs [250,251]. The importance of stereoselectivity in AMPA receptor recognition is highlighted by the higher activity of R-enantiomers such as (-)talampanel.…”

Combined Strategies for the Discovery of Ionotropic Glutamate Receptor Antagonists

“…[16][17][18][19][20] We used the prototypical AMPAR negative modulator GYKI 52466 (1) as lead compound and planned a series of modifications on the 2,3-benzodiazepine skeleton to obtain more potent, less toxic, and longer lasting bioactive molecules (Figure 1). [21][22][23][24] The compounds designed were prepared by conventional procedures and a solid-phase approach.…”

“…Some of these (compounds 2, 3, and 4) showed potent anticonvulsant properties related to a noncompetitive blockade of AMPAR, as confirmed by electrophysiological A C H T U N G T R E N N U N G experiments. [17,18,22] Despite the insightful interest in noncompetitive AMPAR antagonists, there had been no comprehensive study of the structural features that affect their potency and selectivity. Furthermore, little information was available about the location and composition of the AMPAR negative allosteric ligand binding region.…”

Synthesis and anticonvulsant properties of 1,2,3,4-tetrahydroisoquinolin-1-ones

“…[3][4] A selective noncompetitive blockade of AMPA receptor (AMPAR) was shown by some 2,3-benzodiazepine derivatives (Figure 1), [5][6][7][8][9][10] such as the prototype of this family of ligands, 1-(4'-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), and in particular 3-N-acetyl-1-(4'-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-2,3-benzodiazepine (2, Talampanel), which aroused great interest as an anticonvulsant agent and phase II/III clinical trials of which are under way. 11 In our search for new AMPAR negative modulators, [12][13][14][15][16][17][18][19][20][21] Considering that only a little information is available concerning the interaction mechanism of positive and negative modulators 22 and in the absence of three-dimensional structure-based information, we recently developed 23 Our pharmacophore hypothesis was successfully used to design new noncompetitive AMPAR antagonists and led to the discovery of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potent anticonvulsant agents. [24][25][26] In particular, the 2-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 6 ( Figure 1) was characterized by improved pharmacological effects when compared in in vivo and in vitro tests with other current AMPAR antagonists.…”