Benzodiazepines (BDZ)

The first was synthesized by chance in 1960. BDZ completely replaced barbiturates for the treatment of anxety and insomnia).

Therapeutic use of BDZ:

• Reduction of anxiety and aggression.
• Sedation and induction of sleep.
• Anticonvulsant.
• Muscle relaxation and induction and maintenance of anaesthesia.

Classification of BDZ

Long acting benzodiazepines (half-life>48hrs)

• Diazepam
• Fludiazepam
• Halazepam
• Medazepam (prodrug)
• Clorazepate (prodrug) or chlorazepic acid

Intermediate-acting benzodiazepines (24hrs<half-life<48hrs)

• Nitrazepam
• Clonazepam
• Bromazepam

Short-acting benzodiazepines (7hrs<half-life<24hrs)

• Lorazepam
• Temazepam
• Estazolam
• Alprazolam

Ultra-short acting benzodiazepines (1hrs<half-life<7hrs)

• Doxefazepam
• Midazolam
• Triazolam
• Brotizolam

Benzodiazepines full agonist

• Diazepam

Benzodiazepines antagonist

• Flumazenil (it reverses the effects of BDZ by competitive inhibition at the bDZ binding site on GABA receptor. It is used as ANTIDOTE for BDZ OVERDOSE. It reduce excessive daytime sleepiness in case of hypersomnias).

Benzodiazepine partial agonist

• Imidazole

Mechanism of action of BDZ: They bind an allosteric site of the GABA_A receptor localized between the alpha and gamma subunits, causing two effects: increase the receptor affinity for GABA and increase the frequency of the chloride channel opening.

Structure and SARs of BDZ: [see the phrmacophore of BDZ]

• Aromatic ring A, diazepine ring B and carbonyl in 2 are required for affinity.
• Substitution in position 1: position one is a pivotal point of the molecule for metabolism.
• Substitution in 3: removal of the double bond in 4-5 or changing C=O into C=S decrease affinity.
• Substitutions in position 689: decrease the activity.
• Substitution in R1: substitution with electron-withdrawing groups or lipophilic groups increase affinity.
• Substitution in R2: if substituted with little groups (e.g.-CH3) increases the activity.