Benzodiazepines subtypes

Benzodiazepines. Figure 3 Dissection of benzodiazepine pharmacology. The functional roles of GABAa receptor subtypes, mediating particular actions of diazepam, are indicated. A sign indicates that the respective response is mediated by the respective receptor subtype, a sign indicates that the respective response is apparently not mediated by the respective receptor subtype. ND = not determined. 

Rudolph U, Crestani F, Benke D et al (1999) Benzodiazepine actions mediated by specific y-aminobutyric acidA receptor subtypes. Nature 401 796-800... 

McKernan RM, Rosahl TW, Reynolds DS et al (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAa receptor al subtype. Nat Neurosci 3 587-592... 

J, Cook, G, Ferris, P, Garrett, L, Bristow, F, Marshall, G, Macaulay, A, Brown, N, Howell, O, Moore, KW, Carling, RW, Street, LJ, Castro, JF, Ragan, Cl, Dawson, GR and Whiting, PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAa receptor alphal subtype. Nat. Neurosci. 3 587-592. 

A series of 2-phenyl [ 1,2,3 triazolo[l,2-tf][l,2,4]bcnzotriazin-l,5(6//)-diones display submicromolar/nanomolar potency at the central benzodiazepine receptor. The most potent compound 687 (Kj= 2.8 nM) with enhanced affinity is a full agonist at al and aZ receptor subtypes, and has an antagonist efficacy at a5 receptors <2005JME2936>. 

Kralic, J. E., O Buckley, T. K., Khisti, R. T., Hodge, C. J., Homanics, G. E., and Morrow, A. L. (2002) GABAa receptor al subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43, 685-694. 

Crestani, F., Assandri, R., Tauber, M., Martin, J. R., and Rudolph, U. (2002) Contribution of the ai-GABAA receptor subtype to the pharmacological actions of benzodiazepine site inverse agonists. Neuropharmacology 43, 679-684. 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

A therapeutic alternative for treatment of anxiety and depression is the use of 5-HT1A agonists. Azapirones comprise the major class of 5-HT1A agonists of which buspirone (Buspar [4]) is the only FDA-approved 5-HT1A selective agonist (relative to the other 13 serotonin receptor subtypes) for anxiety currently on the US market (Scheme 19.1). Buspirone has shown efficacy in randomized controlled trials of GAD for which it was approved [5-7]. Unlike benzodiazepines, buspirone is not addictive... 

The search for viable partial agonists or subtype selective ligands has led to the development of a variety of compounds representing diverse structural types including imidazoquinoxalines, benzodiazepines, imidazopyridines and -carbolines. In an effort to identify replacement candidates for the partial agonist pandiplon U 78875 206 [289], which was removed from clinical trials due to... 

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