Benzodiazepines.ppt

Benzodiazepines Chris Harvey Medicinal Chemistry April 26, 2007 Overview History Clinical Applications Mechanism of Action Structure General Sub-classes Individual examples Future Research History The first benzodiazepine (benzo) was synthesized by an Austrian scientist named Dr. Leo Sternbach in the mid 1950’s while working at Hoffman-La Roche. The new compound’s potential as a pharmaceutical was not initially recognized, however, Dr. Sternbach’s persistent research eventually uncovered it’s efficacy as a tranquilizer. In 1959, chlordiazepoxide (Librium) was introduced as the first of many benzos to come. Just four years later, in 1963, diazepam (Valium) came on the market. Clinicians quickly recognized the potential of benzos as a safer alternative to the barbiturate class of anxiolytics. Clinical Applications Anxiolytic GAD, PTSD, OCD, etc. Panic Disorder Specific Phobias Anticonvulsant Status epilepticus Myoclonic epilepsy Muscle relaxant Sleep aid Pre-operative anesthesia Alcohol withdrawal Mechanism of Action Benzodiazepines act as GABA (γ-aminobutyric acid) potentiators. They bind to BZ receptors on the GABA-BZ receptor complex, which allows them to allosterically modulate and enhance the activity of GABA. This results in increased hyperpolarization at target neurons, making them less responsive to excitatory stimuli. Structure 2-Keto Benzos Some administered as prodrug All have active metabolites (commonly desmethyldiazepam) Long half-lives (most in excess of 60 hours) 3-hydroxy Benzos No active metabolites Not metabolized in the liver Intermediate half-lives (most ~ 8-20 hours) Triazolo Benzos Additional heterocyclic ring attached at the 1 and 2 positions Some active metabolites Short to intermediate half-lives (anywhere from 3-14 hours) 2-Keto Benzos First isolated benzo Oxidized to desmethyldiazepam in the liver Indicated for treatment of anxiety and insomnia Most prolific and versatile benzo Indicated for treatment of anxiety, seizur