1,5-Benzodiazepines selectivity

Irradiation of the dimers 1 of quinoline 1-imines 2 gives stable 1H-1,2-benzodiazepines. Selected examples are given.122... 

The major uses of individual barbiturates are listed in Table 16-3, mostly uses involving CNS actions of these drugs. As with the benzodiazepines, selection of particular barbiturates for a given therapeutic indication is based primarily on pharmacokinetic considerations. 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

Authors are designed row sensitive and selective test-systems for analysis of heavy metals, active chlorine, phenols, nitrates, nitrites, phosphate etc. for analysis of objects of an environment and for control of ions Ee contents in the technological solutions of KH PO, as well as for testing some of pharmacological psychotropic daigs alkaloids (including opiates), cannabis as well as pharmaceutical preparations of phenothiazines, barbiturates and 1,4-benzodiazepines series too. 

In the case of sodium 2-(diarylmethylene)cyclopentanone tosylhydrazones 3, however, thermolysis gives the 3//-1,2-benzodiazepines 6 in good yield selected examples are shown. It is suggested that steric constraints in the diazo compounds 4 favor the [1,7] ring closure. The reaction proceeds by way of the intermediates 5, which rearrange to the products by a [1,5] shift of hydrogen.115... 

Reduction of the 1//-1,2-benzodiazepines 6 with lithium aluminum hydride results in the dihydro compounds 8, which are dehydrogenated to the 3H-1,2-benzodiazepines 9 by 4-phenyl-4//-l,2,4-triazole-3,5-dione.123 The products readily revert to the 1//-tautomers in the presence of sodium methoxide. 3//-1,2-Benzodiazepines react with 3-chloroperoxybenzoic acid to give mixtures of 1- and 2-oxides, 10 and 11, in which the latter predominate. Treatment of the 2-oxides 11 with nucleophiles provides 3-substituted H- 1.2-benzodiazepines 12. Selected examples are given.124... 

Ring closure of the chloroacetyl compounds 33 yields l,4-benzodiazepine-2,5-diones 34 21-1-214 Selected examples are given.214... 

The standard method for the preparation of 3//-1.5-benzodiazepines 2 is the condensation of benzene-1,2-diamine with 1,3-dicarbonyl compounds. Selected examples are given.255... 

Benzene-1,2-diamine condenses with l-aryl-3,3-disulfanylprop-2-en-l-oncs 12279 to give 1H-1,5-benzodiazepine-2(3//)-thiones 13. Selected examples are given.280... 

Although heating benzene-1,2-diamine with malonic acid in aqueous hydrochloric acid affords the parent dione 26 (R = H) in 62% yield,277 the method cannot be extended to substituted malonic acids because decarboxylation intervenes however, the reaction of benzene-1,2-diamines with diethyl malonate and its derivatives constitutes a general procedure for the synthesis of l,5-benzodiazepine-2,4-diones 26 selected examples are given.278... 

Methylsulfanyl)-37/-l,5-benzodiazepines 11 (vide supra) react with amines by replacement of the methylsulfany group to yield derivatives 12 of 3//-l,5-benzodiazepin-2-amine. Selected examples are given.283... 

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

GABAa receptors are pentameric complexes on the postsynaptic membrane with a central pore with selectivity for chloride ions. Benzodiazepines and barbiturates increase the GABA-induced chloride currents, leading to hyperpolarization of the postsynaptic membrane. 

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... 

Reynaud M, Petit G, Potard D, et al Six deaths linked to concomitant use of buprenor-phine and benzodiazepines. Addiction 93 1383-1392, 1998 Richards JG, Martin JR Binding profiles and physical dependence liabilities of selected benzodiazepine receptor ligands. Brain Res Bull 43 381-387, 1998... 

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... 

Williams H, Oyefeso A, Ghodse AH Benzodiazepine misuse and dependence among opiate addicts in treatment. It J Psychol Med 13 62-64, 1996 Wiseman SM, Spencer-Peet J Prescribing for alcoholics a survey of drugs taken prior to admission to an alcoholism unit. Practitioner 229 88—89, 1985 Wolf B, Grohmann R, Biber D, et al Benzodiazepine abuse and dependence in psychiatric inpatients. Pharmacopsychiatry 22 54—60, 1989 Wood MR, Kim JJ, Han W, et al Benzodiazepines as potent and selective bradykinin B1 antagonists. J Med Chem 46 1803—1806, 2003 Zawertailo LA, Busto UE, Kaplan HL, et al Comparative abuse liability and pharmacological effects of meprobamate, triazolam, and butabarbital. J Clin Psycho-pharmacol 23 269-280, 2003... 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

GABAc receptors are defined by their insensitivity to bicuculline and their activation by conformationally restricted analogues of GABA such as CACA and (+)-CAMP (15, 2i -2-(aminomethyl)cyclopropanecarboxylic acid). They are blocked by picrotoxin but can be selectively antagonised by TPMPA (l,2,5,6-tetrahydropyridin4-ylphosphinic acid). Unlike GABAa receptors, they are not affected by benzodiazepines, barbiturates or anaesthetics (Barnard et al. 1998 Bormann 2000 Chebib and Johnston 2000). 

If excessive noradrenergic transmission is a causal factor in anxiety, then it would be predicted that a lesion of central noradrenergic neurons would have an anti-anxiety effect in behavioural models of this condition. Unfortunately, the behavioural effects of such lesions are notoriously inconsistent and there are many reports of negative findings (e.g. Salmon, Tsaltas and Gray 1989). One study has even shown that a lesion of central noradrenergic neurons, induced by the selective neurotoxin, DSP-4, abolishes the anti-anxiety effects of tricyclic antidepressants and MAO inhibitors, but not those of the benzodiazepine, alprazolam, or the barbiturate, phenobarbitone (Fontana,... 

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