Abstract
A number of new diazonium salt derivatives of 7-chloro-5-phenyl-3-(phenyl-n-substituted)-diazo-1,3-dihydro-benzo[e][1,4]-diazepin-2-one (IVa-l) from 7-chloro-5-phenyl-1,3-dihydro-benzo[e]-[1,4]-diazepin-2-one (III) with diazonium salts (phenyl diazo salt derivatives) were prepared and tested for anticonvulsant activity. The compounds provided significant protection against maximal electroshock induced seizures (MES) and seizures indicated by sc pentetrazole administration (sc PTZ) at 300 mg/kg after 0.5 h. The compounds IVb, IVd, and IVf were active in MES and sc PTZ indicated seizure. A conformational study of these derivatives was undertaken to explore the mechanistic details of the mode of action and their interlinked, interconvertible and energetically favored geometrical configurations acting on the receptor site.
Highlights
Benzodiazepines are bicyclic heterocyclic compounds possessing various types of biological activities over varied N,N-positioned skeletal types [1,2,3]
The benzodiazepines interact with macromolecular membrane complex that has recognition sites for GABA ( -amino butyric acid) at synapses in which GABA is a neurotransmitter as a primary site of action and a chloride ionophore
The benzodiazepines synergistically increase the effects of ionotophoretically applied synaptic GABAA receptor subtype and, elevation of brain GABA transaminase inhibitors increases the electrophysiologic effects of benzodiazepines
Summary
Benzodiazepines are bicyclic heterocyclic compounds possessing various types of biological activities over varied N,N-positioned skeletal types [1,2,3]. Among the large number of benzodiazepines that have been synthesized, the members of 1,4-N,Nbenzodiazepine group have shown sufficient pharmacological activity to warrant introduction as new drugs or templates for tranquilizing, muscle-relaxant, anticonvulsant, and sedative effects while all other benzodiazepine derivatives have marginal or no CNS related bioactivity The use of this class of bioactive derivatives with CNS therapeutic value is confined to anxiety and other neuronal disorders but the minor structural modifications in their structures have produced a host of biologically active products namely Chlordiazepoxide, Diazepam, and Nitrazepam to mention a few acting on a number of CNS related disorders including sleep induction. The binding of drugs to GABA or chloride ionophore can allosterically modify the benzodiazepine receptors, classified as BZ1 and BZ2, and the drug may elicit their action by direct occupation of the benzodiazepine receptor BZ1 or interaction with GABA-chloride ionophore by allosteric interaction complex The metabolism of these classes of compounds has been extensively studied and methods for their analytical detection and blood levels determination have been reported while studying the neurotoxicity associated. We approached to synthesize these compounds with modified structures for stereochemically flexible and interconvertible geometries with an aim for prolonged retention by increasing polarity, improved water solubility, lesser metabolic degradation, better brain impermeation with specified lipophilic endings and better pass-out abilities in metabolicallychallenged subjects [10,11,12,13]
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