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Also known as RO 50690, this drug was the first benzo synthesized in 1960
This benzo is the only drug with an active amine functional group on the "B ring" of the compound
SAR #1 of Benzos:
Ring A must be aromatic: important for interaction with aromatic amino acids of the receptor protein.
Activity increases if the substituent at C7 is electronegative or electronwithdrawing (either nitro or halogen)
Other substituents in 6, 8 or 9 positions decrease activity
SAR #2 of Benzos:
Agonist activity increases when a small alkyl group is attached to N1(ring B), but it is not required for activity
SAR #3 of Benzos:
Keto group at C2 (ring B) or a fused imidazo (midazolam) or triazolo (triazolam and alprazolam) ring present in all but chlordiazepoxide.
- - Portion that binds with the receptor histidine residue
- - Both the keto and electron rich rings act as proton acceptors
SAR #4 of Benzos:
Hydroxyl at C3, ring B (oxazepam) changes the elimination pattern (fasterexcretion, glucuronidation)
SAR #5 of Benzos:
Ring C is not required for in vitro binding, however: Electron withdrawing halogen in position 2' (ortho) of ring C increases agonist activity & Substituents in para position decrease agonist activity (sterichindrance)
They act on the benzodiazepine binding site on the chloride channel of the gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter receptor in the CNS, and increase the frequency of chloride channel opening. This hyperpolarizes the cell and prevents nerve firing/stimulation, resulting in generalized depression of spinal reflexes and the reticular activating system causing CNS depression.
The GABAa receptor complex is a macromolecular chloride chanel that is composed of:
five or more subunits arranged in different combinations surrounding the chloride channel
In order for GABA to work, how many molecules must bind to the receptor to cause hyperpolarization of neuronal function?
BZDs bind to the same site or a different site than GABA??
Different: The BZD site (receptor) is an allosteric modulator that enhances or facilitates GABA binding to the receptor complex. It requires GABA to work --- Shifts GABA dose-response curve to the left
BZD binding results in a conformational change that:
- -Increases Chloride conductance
- -Increases the frequency of channel openings
BZ1 receptor is responsible for causing:
sedation, amnesia and possibly antiseizure effects
BZ2 and BZ3 receptors are responsible for causing:
anxiolytic and muscle relaxant properties
Selective BZ1 receptor agonists include:
zolpidem and eszopiclone --- Have selective sedative/hypnotic actions but very little muscle relaxant or antianxiety effect
This class of drugs bind at a different site at the complex to facilitate GABAand increase chloride conductance: only alpha and beta subunits are required for action --- Primarily increase the maximum height of the GABA dose response curve
Most rapidly and completely absorbed of the PO BZD. Variable bioavailability IM. Rapid and complete distribution into the CNS and other tissues.
This BZD is less lipophilic than diazepam, so it has a slower onset. It also has a slower redistribution into fat which causes a longer duration of action (after single iv dose)
Metabolism of BZDs:
1. Phase I N-dealkylation or hydroxylation (CYP3A4, CYP2C19) to Oxazepam
2. Phase II glucuronidation to inactive metabolites
CNS effects/indications of BZDs:
- 1. Sedation/antianxiety effects
- 2. Anterograde amnesia
- 3. Hypnosis
- 4. Anesthesia
- 5. Antiseizure effects
- 6. Muscle Relaxation
- 7. Treatment of Alcohol & Sedative /hypnotic withdrawal syndromes
Adverse Effects of BZDs:
- 1. Respiratory depression
- 2. Cardiovascular depression
- 3. Teratogenic potential and newborn sedation/withdrawal
- 4. Adverse psychological effects
- 5. Potential for abuse
- 6. BZD discontinuation syndrome
- 7. Sedation/drowsiness/ataxia
Prototypical BZD --- Widest range of indications: anxiety disorders, status epilepticus,skeletal muscle relaxation, anesthetic premedication, drug withdrawal syndromes --- Long-acting BZD (after repeated administration)
No active metabolites --- Indicated for anxiety disorders ---Intermediate-acting BZD
May cause disturbing daytime side effects (disinhibition reactions) --- Indicated for short-term treatment of insomnia --- Short-acting BZD
1. Non BZD structures
2. Selective BZ1 agonists: hypnosis and some amnesia, but minimalmuscle relaxation, antiepileptic and antianxiety effects
3. Indicated for sleep-onset insomnia
Zolpidem and Zaleplon
1. Competitive antagonist of BZD at BZ receptor: has no agonistactions
2. Does not affect GABA, barbiturates, opioids, etc.
3. Used to hasten recovery postoperatively or to treat BZD overdoses
4. Short half life (0.7 to 1.3 hours) requires repeated administration
5. May precipitate sudden withdrawal in BZD-dependent patients
1. Active S(+) isomer of zopiclone (available in Europe as a racemicmixture: Imovane), non-BZD structure.
2. Claims to be active at a different binding site, but classified (bysome) as a BZ1 agonist.
1. First sedative/hypnotic/anxiolytic drugs
2. Some components of action are independent of GABAa receptors
3. Share most of BZD indications
This drug enhances GABA and is a direct agonist at high doses
This drug inhibits GABA reuptake into the presynapticterminal
this drug inhibits GABA metabolism
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