Benzodiazepines AMD

Benzodiazepines The term benzodiazepine is the chemical name for the heterocyclic ring system, which is a fusion between the benzene and diazepine ring systems.  Under Hantzsch–Widman nomenclature, a diazepine is a heterocycle with two nitrogen atoms, five carbon atom. The "benzo" prefix indicates the benzene ring fused onto the diazepine ring. Left: The 1,4-benzodiazepine ring system. Right: 5-phenyl-1H-benzo[1,4]diazepin-2(3H)-one forms the skeleton of many of the most common benzodiazepine pharmaceuticals, such as diazepam (7-chloro-1-methyl substituted)

History…. chlordiazepoxide The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach. Following chlordiazepoxide, diazepam was synthesized in 1959 and marketed by Hoffmann–La Roche under the brand name Valium in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses.

Advantages of Benzodiazepines over Barbiturates….. BZDs have high therapeutic index. Ingestion of even 20 hypnotic doses does not usually endanger life. Hypnotic does not affect respiration or cardiovascular functions. Higher doses produce mild respiration & hypotension which is problematic only in patients with respiratory insufficiency & cardiac abnormality. BZDs have practically no action on other body system BZDs cause little distortion of sleep architecture. BZDs do not alter disposition of other drug by microsomal enzyme induction. They have lower abuse liability: tolerance is mild, psychological & physical dependence & withdrawal syndrome are less marked. A specific BZDs antagonist flumazenil is available which can be used in case of poisoning.

MOA of Benzodiazepines Benzodiazepines work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons. GABA controls the excitability of neurons by binding to the GABAA receptor. The GABAA receptor located in the synapses of neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the GABA, GABAA receptor complexes also contain a single binding site for benzodiazepines. Binding of BDZ to this receptor complex promotes binding of GABA, which in turn increases the conduction of chloride ions across the neuronal cell membrane. resulting in inhibition of neuronal firing.

Types….. Benzodiazepines Hypnotic Antianxiety Anticonvulsant Diazepam. Flurazepam. Alprazolam. Estazolam Flunitrazepam Triazolam Temazepam Quazepam Nitrazepam Midazolam Lormetazepam Chlordiazeperoxide. Lorazepam. Alprazolam Oxazepam Etizolam Clonazepam Clonazepam. Clorazepate Clobazam

Five types of Benzodiazepines Lorazepam Clonazepam Midazolam Alprazolam Diazepam 2-keto compounds: chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, and others. 3-hydroxy compounds: lorazepam, lormetazepam, oxazepam, temazepam 7-nitro compounds: clonazepam, flunitrazepam, nimetazepam, nitrazepam Triazolo compounds: alprazolam, estazolam, triazolam Imidazo compounds : loprazolam, midazolam

Few words about Clonazepam… Pharmacokinetic data Bioavailability 90% Protein binding ~85% Metabolism Hepatic CYP3A4 Half-life 18-50 hours Excretion Renal 5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin-2-one Clonazepam is a benzodiazepine derivative having anticonvulsant, muscle relaxant, and very potent anxiolytic properties. Clonazepam is classified as a high potency benzodiazepine and is sometimes used as a second line treatment of epilepsy due to the development of tolerance to the anticonvulsant effects. Clonazepam is a chlorinated derivative of nitrazepam and therefore a chloro-nitrobenzodiazepine.

Parent Structure…..

SAR Seven membered imino ring B was essential for its affinity towards the BZ-binding site.

SAR Required for activity Additionally, the carbonyl group at position 2, and the 4,5 double bond within the ligand have also been shown to substantially contribute to the binding affinity of the compound.

SAR Shift of double bond to the 3,4 position decreases activity.

SAR An electronegative Substituent at position 7 is required for is required for activity, more the electronegativety higher will be the activity.

SAR Positions at 6,7 & 9 should not be substituted.

SAR A phenyl at position 5 promotes activity. If this phenyl group is ortho or diortho (2’ , 6’) substituted with electron attracting substituents, activity increase.

SAR But para substitution decreases activity greatly. Alkyl substitution at position 3 decreases activity except hydroxy group.

SAR The presence or absence of 3-hydroxyl is important pharmacokinetically. Compounds without hydroxyl group are non polar, have long half lives & undergo hepatic oxidation. Non polar. Long half-lives. Undergo hepatic oxidation. OH H/COO– Polar. Readily converted to the excreted glucuronide.

SAR The 2-carbonyl function is optimal for activity.

SAR R1 substitution should be small.

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