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SAR OF BENZODIAZEPINES By . Jyotirmoy Das Choudhury M.Pharm 2nd semester Phamacology Under the Guidance of Miss. Sai Prasanna Behera ( M.Pharm ), Lecturer, Pharmacology Department. RCPHS


Content…. Introduction. History. Types. Synthesis. Mechanism of Action. Uses. Parent compound. Requirement of SAR Study. SAR Study. Conclusion. References. 2

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BENZODIAZEPINES The term benzodiazepine is the chemical name for the heterocyclic ring system, which is a fusion between thebenzene and diazepine ring systems.  Under Hantzsch–Widman nomenclature, a diazepine is a heterocycle with two nitrogen atoms, five carbon atom and the maximum possible number of cumulative double bonds. The " benzo " prefix indicates the benzene ring fused onto the diazepine ring. 4

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Left : The 1,4-benzodiazepine ring system. Right : 5-phenyl-1 H -benzo[ e ][1,4]diazepin-2(3 H )-one forms the skeleton of many of the most common benzodiazepine pharmaceuticals, such asdiazepam (7-chloro-1-methyl substituted) Contd…. 5


History…. 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. 6


Contd …… In 2010, formerly classified documents from a Medical Research Council (UK) meeting of experts emerged and revealed that benzodiazepines could cause brain damage in some people similar to that which occurs from alcohol abuse and failed to follow-up with larger clinical trials. The molecular structure of chlordiazepoxide , the first benzodiazepine. It was marketed by Hoffmann–La Roche from 1960 branded as Librium . 7


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 8


Contd …… 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. 9


MOA of BENZODIAZEPINES Benzodiazepines work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain. GABA controls the excitability of neurons by binding to the GABA A receptor. The GABA A receptor is a protein complex located in the synapses of neurons. All GABA A receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter gamma- aminobutyric acid (GABA), while a subset of GABA A receptor complexes also contain a single binding site for benzodiazepines. 10


Contd …… Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the conduction of chloride ions across the neuronal cell membrane. This increased conductance raises the membrane potential of the neuron, resulting in inhibition of neuronal firing. Schematic diagram of the (α1) 2 (β2) 2 (γ2) GABA A receptor complex 11


Types….. Benzodiazepines Hypnotic Antianxiety Anticonvulsant Diazepam. Flurazepam . Alprazolam . Diazepam. Chlordiazeperoxide . Lorazepam . Diazepam. Lorazepam . Clonazepam . 12

Few words about CLONAZIPAM…: 

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 . Clonazepam , like other benzodiazepines, while being first line treatments for acute seizures, are not first line for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects. 13 Few words about CLONAZIPAM…


Clonazepam is a chlorinated derivative of nitrazepam and therefore a chloro-nitrobenzodiazepine . 14 Contd …… 5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin-2-one Pharmacokinetic data Bioavailability 90% Protein binding ~85% Metabolism Hepatic CYP3A4 Half-life 18-50 hours Excretion Renal

Parent Structure…..: 

Parent Structure….. 15

SAR Study….: 

Seven membered imino ring B was essential for its affinity towards the BZ-binding site. SAR Study…. 16


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. Required for activity Contd …… 17


Shift of double bond to the 3,4 position decreases activity. Contd …… 18


An electronegative Substituent at position 7 is required for is required for activity, more the electronegativety higher will be the activity. Contd …… 19


Contd …. Positions at 6,7 & 9 should not be substituted. 20


A phenyl at position 5 promotes activity. If this phenyl group is ortho or diortho (2’ , 6’) substituted with electron attracting substituents , activity increase. Contd …. 21


But para substitution decreases activity greatly. Alkyl substitution at position 3 decreases activity except hydroxy group. Contd …. 22


The presence or absence of 3-hydroxyl is important pharmacokinetically . Compounds without hydroxyl group are non polar, have long half lives & undergo hepatic oxidation. Contd …. OH H/COO – Polar. Readily converted to the excreted glucuronide . N on polar. Long half-lives. Undergo hepatic oxidation. 23


The 2-carbonyl function is optimal for activity. Contd …. 24


R 1 substitution should be small. Contd …. 25

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