| Candidate ID: | R0143 |
| Source ID: | DB00404 |
| Source Type: | approved; illicit; investigational |
| Compound Type: |
small molecule
|
| Compound Name: |
Alprazolam
|
| Synonyms: |
8-Chloro-1-methyl-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine; Alprazolam
|
| Molecular Formula: |
C17H13ClN4
|
| SMILES: |
CC1=NN=C2CN=C(C3=CC=CC=C3)C3=C(C=CC(Cl)=C3)N12
|
| Structure: |
|
| DrugBank Description: |
Alprazolam is a triazolobenzodiazepine indicated for the treatment of anxiety and panic disorders. It is mainly metabolized by CYP3As and so is contraindicated with CYP3A inhibitors like ketoconazole and itraconazole. Benzodiazepine treatment should be stopped gradually by tapering down a patient's dose to avoid withdrawal symptoms. Alprazolam's adverse effects are generally related to the sedation it can cause. Alprazolam has been mixed with alcohol as a drug of abuse to potentiate the sedative effects of the drug which may lead to coma and death. Alprazolam was given FDA approval on October 16, 1981.
|
| CAS Number: |
28981-97-7
|
| Molecular Weight: |
308.765
|
| DrugBank Indication: |
Alprazolam is indicated for the acute treatment of generalized anxiety disorder in adults. Alprazolam is also indicated, either as a standard or extended-release formulation, for the treatment of panic disorder with or without agoraphobia in adults.
Alprazolam may also be prescribed off-label for insomnia, premenstrual syndrome, and depression.
|
| DrugBank Pharmacology: |
Alprazolam is a benzodiazepine that binds γ-aminobutyric acid (GABA) type-A receptors (GABA<sub>A</sub>Rs) to enhance their inhibitory effect on neurotransmission, specifically in the brain. Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death; patients taking benzodiazepines and opioids concurrently may require lower doses of one or both medications, depending on their clinical situation. Patients with pre-existing impaired respiratory function are at increased risk of adverse effects including death during treatment with benzodiazepines. In addition, due to its CNS depressant effects, patients taking alprazolam should avoid operating heavy machinery or driving and should avoid other CNS depressants such as alcohol. As with other benzodiazepines, alprazolam carries a risk of abuse, misuse, and addiction, which is higher in predisposed individuals and may require strict monitoring. Cessation of therapy may result in acute or protracted withdrawal symptoms, which may be life-threatening; the patient dose should be gradually tapered whenever discontinuation or reduced dosage are necessary. Newborns born to mothers using alprazolam later in pregnancy may suffer from sedation and withdrawal symptoms. As CYP3A is required for the initial step in alprazolam metabolism, alprazolam is contraindicated in patients taking strong CYP3A inhibitors, such as ketoconazole and itraconazole; milder CYP3A inhibitors still necessitate alprazolam dosage adjustments. Lastly, benzodiazepines may have negative effects, such as panic disorders, increased suicide incidence, and episodes of mania/hypomania, in patients suffering from depression.
|
| DrugBank MoA: |
Neurotransmission relies on excitatory and inhibitory signalling. γ-aminobutyric acid (GABA) type-A receptors (GABA<sub>A</sub>Rs) are members of the pentameric ligand-gated ion channel (PLGIC) superfamily located synaptically and perisynaptically to mediate phasic inhibition and extrasynaptically to mediate tonic inhibition. GABA<sub>A</sub>Rs comprise a variety of subunits from a homologous family whose members are named based on sequence identity as one of α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3. Each subunit possesses an extracellular (ECD), transmembrane (TMD), and intracellular (ICD) domain; inter-subunit interfaces are the primary points of neurotransmitter and modulator binding, described by coordination of the principal (+) and complementary (-) sites in each subunit. Binding of GABA to GABA<sub>A</sub>Rs induces pore opening, rapid flow of chloride ions, and synaptic hyperpolarization, which in turn manifests as an inhibitory signal.
The most prevalent GABA<sub>A</sub>Rs _in vivo_ are the α1β2γ2 receptors, which contain both GABA (β+/α-) and benzodiazepine (BZD, α+/γ-) binding sites in the intersubunit interfaces of the relevant subunits. In general, any receptors containing an α<sub>x</sub>/γ<sub>z</sub> interface, where x = 1-3,5 and z = 1-3, have potential high-affinity BZD binding sites, although small sequence differences between subunits may alter binding affinity to individual molecules. The α4 and α6 subunits, in which an otherwise conserved histidine is replaced by arginine, do not bind traditional BZD ligands such as diazepam and hence are considered "diazepam-insensitive". GABA binding results in a series of conformational changes in the ECDs of GABA<sub>A</sub>R β subunits, "locking" each to its neighbouring α- interface. The binding of alprazolam in the high-affinity BZD site stabilizes the α+/γ- interface and facilitates the conformational changes that lead to pore opening, hence functioning as a positive allosteric modulator.
The exact manner in which GABA<sub>A</sub>R allosteric modulation mediates the therapeutic and unwanted effects of benzodiazepines remains unclear. Earlier studies suggested that the primary factor was the α subunit composition, with α1-containing receptors mediating the sedative effects, α2/3-containing receptors the anxiolytic effects, and α5-containing receptors the memory effects of benzodiazepines. More recent studies suggest a more complex set of factors including subunit composition, physiological location, neuronal circuit, and nerve cell type. To further complicate matters, there may be up to five distinct BZD binding sites on GABA<sub>A</sub>Rs, with site 1 corresponding to the classical high-affinity α+/γ- interface. The effects of binding at sites 2-4 are not fully understood and likely impart greater complexity to benzodiazepine pharmacological action.
|
| Targets: |
GABA(A) Receptor positive allosteric modulator; GABA(A) Receptor Benzodiazepine Binding Site ligand
|
| Inclusion Criteria: |
Indication associated
|
