Tamas Hamori

New Non Competitive AMPA Antagonists

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.

Anxiolytic 2,3-benzodiazepines, their specific binding to the basal ganglia.

Over the past 20 years, several members of the 2,3-benzodiazepine family have been synthesized. Some of these compounds--tofisopam (Grandaxin), girisopam, nerisopam--exert significant anxiolytic and antipsychotic activities. Sites where actions of 2,3-benzodiazepines are mediated differ from those of 1,4-benzodiazepines. Binding of 2,3-benzodiazepines to neuronal cells in the central nervous system shows a unique and specific distribution pattern: their binding sites are located exclusively to the basal ganglia. Chemical lesioning of the striato-pallido-nigral system, surgical transections of the striato nigral pathway and the activation of c-fos expression in the basal ganglia after application of 2,3-benzodiazepines suggest that these compounds mainly bind to projecting neurons of the striatum. The binding sites are transported from the striatum to the substantia nigra and the entopeduncular nucleus. Recent studies on mechanism of action of 2,3-benzodiazepines indicate their possible role in opioid signal transduction since 2,3-benzodiazepines augment the agonist potency of morphine to induce catalepsy and analgesia, and their action is diminished in morphine tolerant animals. The possible biochemical target of 2,3-benzodiazepines is an alteration in the phosphorylation of protein(s) important in the signal transduction process. Agents affecting emotional responses evoked by endogenous opioids without danger of tolerance and dependence may represent a new therapeutic tool in the treatment of addiction and affective disorders.

Asymmetric reduction of a carbon–nitrogen double bond: enantioselective synthesis of 4,5-dihydro-3H-2,3-benzodiazepines

A highly specific enantioselective reduction, elaborated for the reduction of the 3,4-carbon–nitrogen double bond of 4-methyl-7,8-methylenedioxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine 4 made possible the synthesis of the enantiomers of the potent non-competitive AMPA/kamate antagonists 2a, b. NMR Investigations of the reducing complex show that there is no formation of an 1,3,2-oxazaborolidine ring as may have been presumed on the basis of literature data.

Structural analogues of some highly active non-competitive AMPA antagonists

Some 5-methyl analogues (14a-e) of the non-competitive AMPA antagonists 3-acylated 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3H-2,3-benzodi azepines (2,3) have been synthesized. Generally they show diminished or low biological activity but two derivatives (14a,b) reveal effects comparable to those of GYKI 52466 (1), the prototype non competitive AMPA antagonist.