1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones:  Novel AMPA Receptor Antagonists

Abstract

Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. 1-(4'-Aminophenyl)- (38) and 1-(3'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin- 4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED50 values against tonus evoked by auditory stimulation were 12.6 micromol/kg for derivative 38, 18.3 micromol/kg for 39, and 25.3 micromol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [3H]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.

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.…”

Application of ortho-acylated phenylacetic acid esters to the synthesis of 1-substituted isochromanes

“…The key step for the synthesis of the isochromane nucleus is an oxidative mercury-mediated ring closure of phenylmethanol derivatives or the ozonolysis of the corresponding phenylmethanol derivative. 32,33 The hydroxyisochromanes were prepared also by saponification of 5-formylmellein, 34 reduction of dimethoxyphenethyl alcohol with aromatic aldehydes, [2][3][4] or cyclization with p-toluenesulfonic acid. 47 In a search for new approaches to the synthesis of isochromanes, we found that they can be obtained from the corresponding ethyl-(or methyl-) 2-acylphenylacetates 3 in very good yields.…”

“…1 Many isochromanes have been synthesized as intermediates of the synthesis of anxiolytic 2,3-benzodiazepines, which are known as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. [2][3][4] Recently, Nergardh et al reported that isochroman A 68930 is a selective dopamine D1 antagonist. 5 Some isochromanes are pharmacologically active compounds in anti-migraine therapy.…”

3D Pharmacophore Models for 1,2,3,4‐Tetrahydroisoquinoline Derivatives Acting as Anticonvulsant Agents

“…In particular, some 2,3-benzodiazepines (1 -3, Fig. 1) [4,5] were identified as marked antiepileptic agents in various seizure models interacting with AMPA receptor complex in a selective and noncompetitive fashion. Among them, talampanel 1 has shown positive results in patients with severe epilepsy not responsive to other drugs and phase III trials are under way to confirm these results [6].…”