Benzodiazepines function

Neither the oxide nor the amidine function are in fact required for activity. Treatment of the oxime, 7, with chloro-acetyl chloride in the presence of sodium hydroxide proceeds directly to the benzodiazepine ring system (14)(the hydroxyl ion presumably fulfills a role analogous to methylamine in the above rearrangement). Reduction of the N-oxide function of 14 leads to diazepam (15). ... 

The anxiolytic agent buspirone (131) is notable for the fact that it does not interact with the receptor for the benzodiazepines. This difference in biochemical pharmacology is reflected in the fact that buspirone (131) seems to be devoid of some of the characteristic benzodiazepine side effects. The spiran function is apparently not required for anxiolytic activity. Alkylation of 3,3-dimethylglutarimide with dichlorobutane in the presence of strong base yields the intermedi-... 

Aminobenzylamine (1, R1 = H) reacts with benzil in refluxing acetic acid for 24 hours to give the yellow 2,3-diphenyl-5//-l,4-benzodiazepine (2) in 47% yield, but the reaction is not general. However, 2-chloro-2//-azirines function as diketone equivalents, yielding the benzodiazepines 3, when treated with equivalent amounts of the diamines 1 in pyridine at 20 C. Further details were not reported.192... 

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. 

Low K, Crestani F, Keist R, et al Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 131-134, 2000 Luddens H, Pritchett DB, Kohler M, et al Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 346 648—651, 1990 LupoloverY, Safran AB, Desangles D, etal Evaluation ofvisual function in healthy subjects after administration of Ro 15-1788. Eur J Clin Pharmacol 27 505-507, 1984 Maher JF, Schreiner GE, Westervelt FB Jr Acute glutethimide intoxication 1. clinical experience (twenty-two patients) compared to acute barbiturate intoxication (sixty-three patients). Am J Med 33 70-82, 1962 Marks J The Benzodiazepines Use, Overuse, Misuse, Abuse. Baltimore, MD, University Park Press, 1978... 

Miller LG, Greenblatt DJ, Barnhill JG, et al Chronic benzodiazepine administration, I tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function. J Pharmacol Exp Ther 246 170-176, 1988a... 

Van Sickle BJ, Tietz El Selective enhancement of AMPA receptor-mediated function in hippocampal CAl nemons from chronic benzodiazepine-treated rats. Nemo-pharmacology 43 11—27, 2002... 

Setting aside the general anaesthetics, which do not directly modify the function of any particular neurotransmitter, all the drugs that are used to induce sleep, i.e. the hypnotics , augment the function of GABA and so directly depress neuronal function and probably facilitate cortico-thalamic synchrony. Most of them are benzodiazepines... 

A benzodiazepine template was also reported by researchers at GlaxoSmithKline [85]. The lead molecule GW405212, (40), was identified from a 1,296-member library of 1,4-benzodiazepines prepared on Tentagel beads and screened initially in pools of 30 against CHO cells expressing the human oxytocin receptor. It is a highly potent inhibitor of oxytocin binding with a K of 8nM [86]. However, all attempts to improve the pharmacokinetic properties of this molecule were unsuccessful. It appears that the functionality responsible for the oxytocin activity is distributed around the periphery... 

Evidence for the false transmitter theory as the cause of encephalopathy is demonstrated by the fact that administration of flumazenil (a benzodiazepine antagonist) has resulted in functional improvement. Unfortunately, long-term benefit has not been shown, and since flumazenil can only be administered par-enterally, it is not an appropriate choice for long-term therapy. 

Assess patients for improvement of anxiety symptoms and for return to baseline occupational, social, and interpersonal functioning. With effective treatment, the patient should have no or minimal symptoms of anxiety or depression. While drug therapy is being initiated, evaluate patients more frequently to ensure tolerability and response. Increase the dose in patients exhibiting a partial response after 2 to 4 weeks on an antidepressant or 2 weeks on a benzodiazepine. Individualize the duration of treatment because some patients require up to one year of treatment.27... 

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