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Benzodiazepines
Dr.Narmin Hamaamin Hussen
College Of Pharmacy
Medicinal Chemistry III / 4th Stage/ 1st Semester
Lecture 1
2023-2024
2
Benzodiazepines
▪ Benzodiazepines are a psychiatrist's drug class with sedative, hypnotic, anxiolytic, anticonvulsant, and muscle
relaxant effects.
▪ They work by increasing the inhibitory effects of the neurotransmitter gamma-aminobutyric acid (GABA) in the
brain, resulting in greater relaxing or sedative activity
▪ These drugs are often used to treat anxiety, sleeplessness, seizures, muscle spasms, and the symptoms of
alcohol withdrawal..
3
▪ 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.
▪ 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.
History of Benzodiazepines
GABAA Receptors
4
▪ GABA is the most common and major inhibitory neurotransmitter (NT) in the
brain and it exerts its rapid inhibitory action mostly through GABA
receptors.
▪ GABA system is important in the pathophysiology of anxiety and insomnia.
▪ GABAA receptor is the target for many anxiolytics and sedative–hypnotic
agents including benzodiazepines, barbiturates, zolpidem, zaleplon,
eszopiclone, steroids, anticonvulsive agents, and many other drugs that
bind to different binding sites of the GABAA receptors in neuronal
membranes in the CNS
5
Mechanism of Action benzodiazepines
Benzodiazepines
6
▪ Benzodiazepines (BZD, BDZ), sometimes called "benzos", are the bicyclic heterocyclic
compounds in which benzene ring (A)is fused to seven membered diazepine ring(B)
containing two nitrogen.
▪ 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
▪ Numbering is started from adjacent nitrogen to the bridge heads and second nitrogen is
given 4th position. That’s why these drugs are called 1,4-benzodiazpines.
▪ Most benzodiazepines are 5-aryl-1,4-benzodiazepines and contain a carboxamide group
in the seven-membered diazepine ring structure.
5-aryl

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Benzodiazepines--Medicinal Chemistry

  • 1. Benzodiazepines Dr.Narmin Hamaamin Hussen College Of Pharmacy Medicinal Chemistry III / 4th Stage/ 1st Semester Lecture 1 2023-2024
  • 2. 2 Benzodiazepines ▪ Benzodiazepines are a psychiatrist's drug class with sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant effects. ▪ They work by increasing the inhibitory effects of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain, resulting in greater relaxing or sedative activity ▪ These drugs are often used to treat anxiety, sleeplessness, seizures, muscle spasms, and the symptoms of alcohol withdrawal..
  • 3. 3 ▪ 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. ▪ 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. History of Benzodiazepines
  • 4. GABAA Receptors 4 ▪ GABA is the most common and major inhibitory neurotransmitter (NT) in the brain and it exerts its rapid inhibitory action mostly through GABA receptors. ▪ GABA system is important in the pathophysiology of anxiety and insomnia. ▪ GABAA receptor is the target for many anxiolytics and sedative–hypnotic agents including benzodiazepines, barbiturates, zolpidem, zaleplon, eszopiclone, steroids, anticonvulsive agents, and many other drugs that bind to different binding sites of the GABAA receptors in neuronal membranes in the CNS
  • 5. 5 Mechanism of Action benzodiazepines
  • 6. Benzodiazepines 6 ▪ Benzodiazepines (BZD, BDZ), sometimes called "benzos", are the bicyclic heterocyclic compounds in which benzene ring (A)is fused to seven membered diazepine ring(B) containing two nitrogen. ▪ 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 ▪ Numbering is started from adjacent nitrogen to the bridge heads and second nitrogen is given 4th position. That’s why these drugs are called 1,4-benzodiazpines. ▪ Most benzodiazepines are 5-aryl-1,4-benzodiazepines and contain a carboxamide group in the seven-membered diazepine ring structure. 5-aryl
  • 7. 7 Structure–activity relationships (SARs) of benzodiazepines 1st position ▪ At 1st position, a small alkyl group is optimal for activity. ▪ For example, diazepam and temazepam has methyl group at 1st position
  • 8. ▪ Also, flurazepam has diethylaminoethyl group but it doesn’t add any advantage to their action. ▪ Alkyl group is not essential as few of the benzodiazepines don’t have any alkyl at 1st position. For example, benzodiazepines like oxazepam, lorazepam and nitrazepam simply have hydrogen at 1st position. 1st position
  • 9. 2nd position ▪ A carbonyl group at 2nd position is essential for activity ▪ Second position is very important in view of pharmacological activity as the drugs bind to benzodiazepine receptor through this group. ▪ You can easily observe this group in many of the benzodiazepines such as diazepam, oxazepm etc. 2 1 3 4 5 6 7 8 9
  • 10. 2nd position ▪ Here we can found two exceptions. First is at chlordiazepoxide and second at fused benzodiazepines. ▪ Chlordiazepoxide is the first benzodiazepine that was developed and it doesn’t have keto group at 2nd position ▪ But in-vivo it can undergo oxidative deamination to produce demoxepam with keto group at second position. ▪ This again proved that keto group at 2nd position is essential for activity.
  • 11. ▪ Fused benzodiazepines like alprazolam, midazolam and triazolam interact with GABA receptors through triazole or imidazole ring. 2 2 2 2nd position Imidazolobenzodiazepine Triazolobenzodiazepine
  • 12. 3rd position ▪ This position is very important in view of pharmacokinetics. ▪ It is obvious that drugs or metabolites which are highly polar can undergo direct conjugation and hence directly excreted. ▪ A polar functional group at 3rd position increases excretion thereby decrease duration of action. ▪ Drugs like lorazepam, oxazepam and temazepam have hydroxyl group at 3rd position making all these drugs polar and easily excretable. Hence all these drugs have short duration of action 3 3 3
  • 13. ▪ Oxazepam and lorazepam are highly polar and can be excreted without phase I metabolism. 3rd position
  • 14. 3rd position With Carboxylic acid Clorazepate dipotassium ▪ Inactive itself, it undergoes rapid decarboxylation by the acidity of the stomach to nordazepam (a major active metabolite of diazepam), which has a long half-life and undergoes hepatic conversion to active oxazepam. ▪ Despite the polar character of the drug as administered, because it is quickly converted in the GI tract to an active nonpolar compound, it has a quick onset, overall long half-life, and shares similar clinical and pharmacokinetic properties to chlordiazepoxide and diazepam Metabolism of Clorazepate dipotassium
  • 15. 3rd position Without hydroxyl group ▪ Benzodiazepines without the hydroxyl group are nonpolar and undergoes Phase I and Phase II metabolic pathways: hepatic oxidation and reduction (by cytochrome P450) and glucuronide conjugation. ▪ Most benzodiazepines are lipophilic, in the nonionized form and thus well absorbed from the GI tract, whereas the more polar compounds (e.g., those with a 3-hydroxyl group) tend to be absorbed more slowly than the more lipophilic compounds. ▪ These drugs tend to be highly bound to plasma proteins; in general, the more lipophilic the drug, the greater the binding. ▪ The more lipophilic a benzodiazepine, the higher the rate of absorption and faster the onset of clinical action. For example, diazepam and midazolam have the highest lipid solubility and therefore also the quickest onset of action ▪ Drugs like Chlordiazepoxide, diazepam, nitrazepam, Prazepam, Halazepam and Flurazepam, without hydroxyl group at 3rd position making all these drugs nonpolar and slowly excretable. Hence all these drugs have long duration of action.
  • 16. Diazepam ▪ Diazepam (Valium) is prototypical and was the first member of the benzodiazepine-2-one group to be introduced. ▪ It is very lipophilic and is thus rapidly and completely absorbed after oral administration. ▪ Maximum peak blood concentration occurs in 2 hours and elimination is slow, with a half-life of about 46 hours. ▪ As with chlordiazepoxide, diazepam is metabolized by N-demethylation to active nordazepam, which is 3- hydroxylated to active oxazepam by CYP2C19 and CYP3A4. ▪ Like chlordiazepoxide, repeated administration of diazepam leads to accumulation of an active nordazepam Nordazepam Metabolism of Diazepam
  • 17. Triazolobenzodiazepine : Metabolism of Triazolobenzodiazepine and Imidazolobenzodiazepine: ▪ Alprazolam is one of the drugs widely used for anxiety disorders. It is a medium acting benzodiazepine with duration of action as 24 hrs. Hence it is given once a daily. ▪ Triazolam is a ultra short acting benzodiazepine with duration of action less than 6 hrs. Due to short action it can be used as hypnotic.
  • 18. Imidazobenzodiazepine: ▪ Midazolam is not used anxiolytic but used in induction of anesthesia by IV route.
  • 19. ▪ Based on drug elimination (metabolism + kidney filtration), 3 category of benzodiazepines exist. Half-life Example Long acting More than 24 hrs. Diazepam, Nitrazepam chlordiazepoxide, flurazepam Intermediate acting 12-24 hrs. alprazolam, lorazepam clonazepam, flunitrazepam Short acting Less than 1-12 hrs. midazolam and triazolam ▪ longer-acting benzodiazepines are recommended for the treatment of anxiety ▪ Short- and intermediate-acting are preferred for the treatment of insomnia 3rd position
  • 20. 4th position ▪ In all benzodiazepines we can observe an unsaturation at 4th and 5th position. ▪ This is essential for activity and saturation of this double bond may decrease the activity. ▪ Even shift of the double bond to 3rd and 4ht position decreases the activity. 4 5 Essential for activity
  • 21. 5th position ▪ A simple aromatic ring like phenyl group is optimal for activity. ▪ Again all benzodiazepines including fused benzodiazepine ring systems have a phenyl group at 5th position. ▪ For example, drugs like diazepam, nitrazepam, oxazepam, temazepam and chlordiazepoxide all have a phenyl group at 5th position. ▪ Substitution on phenyl group also plays a key role in influencing activity ▪ But all positions may not yield favourable results. Those drugs having phenyl group with ortho or diorhto substitution with an electron withdrawing group found to increase activity. At the same time, para substitution decreases the activity. Para
  • 22. ▪ We can easily observe this in the names of few benzodiazepines. ▪ For example, flurazepam has fluoro group and clonazepam has chlorine group ✓ Note: ▪ This applies to above two drugs only. Don’t think that nitrazepam has nitro group on phenyl ring. Actually it has nitro group at 7th position of the benzodiazepine ring. ▪ Similarly other drugs like triazolam and midazolam has chlorine and fluorine groups respectively at ortho position of the phenyl ring.
  • 23. 7th position ▪ This is again very important position to determine the potency of benzodiazepine. ▪ Electron withdrawing groups like halogens or nitro group increase the activity. ▪ Higher the electornegativity higher the potency ▪ Therefore nitrazepam is more potent than diazepam ▪ The EA property of the nitro group is associated with the fact that all three atoms of this group are strongly electronegative 7
  • 24. ▪ Nonbenzodiazepines sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are benzodiazepine-like in uses, such as for treating insomnia and anxiety. Nonbenzodiazepines ▪ Nonbenzodiazepine pharmacodynamics are similar in mechanism of action to benzodiazepine drugs, acting as GABAA receptor positive allosteric modulators of the benzodiazepine site, and therefore exhibit similar benefits, side effects, and risks. However, nonbenzodiazepines have dissimilar or entirely different chemical structures, so are unrelated to benzodiazepines on a molecular level
  • 25. Currently, the major chemical classes of nonbenzodiazepines are: 1. Imidazopyridines Alpidem Necopidem Saripidem Zolpidem 2. Pyrazolopyrimidines Divaplon Fasiplon Indiplon Lorediplon Ocinaplon Panadiplon Taniplon Zaleplon 3. Cyclopyrrolones Eszopiclone Pagoclone Pazinaclone Suproclone Suriclone Zopiclone
  • 26. ▪ Zolpidem (imidazopyridine) and eszopiclone (cyclopyrrolone) are nonbenzodiazepines and have been introduced as short and moderate-acting hypnotics, respectively. ▪ Zolpidem exhibits a high selectivity for the α1 subunit of benzodiazepine binding site on GABAA receptor complex. ▪ Zolpidem has a rapid onset of action of 1.6 hours and good bioavailability (72%), mainly because it is lipophilic and has no ionizable groups at physiological pH. ▪ It has short elimination half-life, because its aryl methyl groups is extensively αhydroxylated to inactive metabolites by CYP3A4 followed by further oxidation by aldehyde dehydrogenase to the ionic carboxylic acid. ▪ The metabolites are inactive, short-lived, and eliminated in the urine. Its half-life in the elderly or the patients with liver disease is increased. N-demethylation
  • 27. Zaleplon ▪ Zaleplon is another short-acting nonbenzodiazepine hypnotic. ▪ Pharmacologically and pharmacokinetically, zaleplon is similar to zolpidem; both are hypnotic agents with short halflives. ▪ It also has selective high affinity for α1-subunit containing BzRs but produces effects at other BzR/GABAA subtypes as well ▪ It is primarily metabolized by aldehyde oxidase to 5-oxo-zaleplon and is also metabolized to a lesser extent by CYP3A4. N- demethylation yields desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon. ▪ These oxidative metabolites are then converted to glucuronides and eliminated in urine. ▪ All of zaleplon’s metabolites are pharmacologically inactive. It may have a more rapid onset (about 1 hour) and termination of action than zolpidem, and therefore, it is good to initiate sleep instead of keeping sleep
  • 28. Benzodiazepines and related compounds can act as antagonists, at the benzodiazepine-binding site on GABAA receptor Fluoroquinolones ▪ FDA updates warnings for fluoroquinolone antibiotics on risks of mental health and low blood sugar adverse reactions in July 10, 2018. ▪ Fluoroquinolones are antagonists of the GABA-A receptor, meaning that they prevent the binding of GABA and can displace other molecules bound to the receptor, such as benzodiazepines. ▪ GABA is an inhibitory neurotransmitter and drugs which enhance its action, like benzodiazepines, cause sedation. ▪ The GABA receptor blockade caused by a fluoroquinolone results in a CNS stimulant effect, with neurological manifestations ranging from mild insomnia and agitation to hallucinations and seizures. •https://doi.org/10.1080/01480545.2023.2240036
  • 29. Antidote for benzodiazepine toxicity Flumazenil ▪ Flumazenil, a specific benzodiazepine antagonist, is useful in reversing the sedation and respiratory depression that often occur when benzodiazepines. ▪ Antagonist at the benzodiazepine receptor.
  • 30. Exercise 1- Regarding the structure activity relationships (SARs) of benzodiazepines
  • 31. 3 1 2. The benzodiazepines listed below have been rearranged from short-acting to long-acting. A B C D