The Anxiolytic Agents

The anxiolytic agents consist of benzodiazepine derivatives and azaspirodecanedione derivatives. 

The benzodiazepine derivatives class of antianxiety agents shares the property of binding to a benzodiazepine receptor, part of the GABA receptor-chloride channel complex whose function it modulates allosterically. Not only the anxiolytic effects of the benzodiazepines, but also the anticonvulsant, sedative, or muscle relaxant effects seem to be mediated by the GABA-related mechanism. Besides the direct involvement of the GABA system, in parallel or more downstream to this, several other neurotransmitters such as serotonin have been suggested to participate in different aspects of benzodiazepine action. 

The azaspirodecanedione derivatives include buspirone, gepirone, and ipsapirone. 

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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-... 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Condensation of this with ethyl orthoacetate gives the anxiolytic agent brotizolam (167) [31]. 

A simple and efficient procedure for the direct oxidation of C-3 of l,4-benzodiazepin-2-ones, applicable to the preparation of the anxiolytic agents oxazepam and lorazepam, has been developed that represents an improvement over the well-established Polonovsky rearrangement of the N-4 oxide <20060PD1192>. Iodine in AcOH at 65 °C catalyzed acetoxylation in a reaction that involved iodination at C-3 followed by a rapid nucleophilic displacement by KOAc. The liberated HI was recycled to iodine by inclusion of a stoichiometric oxidant, with K2S2O8 being the optimal compromise of cost, availability, and efficiency. 

Needham, S. R. Cole, M. J. Fouda, H. G. 1998. Direct plasma injection for high-performance liquid chromatographic-mass spectrometric quantitation of the anxiolytic agent CP-93 393. J. Chromatogr. B, 718,87-94. 

Benzo derivatives are well known (Figure 4) and some are the basis of important therapeutic agents such as the tricyclic antidepressant clomipramine 3 and the anxiolytic agent diazepam 4. In these molecules the seven-membered rings act as extremely good scaffolds that allow a wide variety of substituent variation and exploration of conformational space during the discovery phase of drug development. 

Rapoport DM, Greenberg HE, Goldring RM. Differing effects of the anxiolytic agents buspirone and diazepam on control of breathing. Clin Pharmacol Ther 1991 49(4) 394-401. 

According to the chemical structure, the anxiolytic agents used in allopathic medicine may be divided into three classes carbamate of propanodiol and related compounds, BZDs and several others compounds. The most effective are the BDZs Chlordiazepoxide, Fig. (3), which was commercialized in 1960 as a therapeutic innovation for the treatment of anxiety. As from the identification of its property, dozens of new BDZs derivates were commercialized, including diazepam. Fig. (3), one of the medicines most prescribed worldwide. 

Figure 6-11 Differential metabolism of the anxiolytic agents alpidem (hepatotoxin) and Zolpidem (non-hepatotoxin).

The anxiolytic agents currently on the market owe much to serendipity as well as rational design in their genesis. With the exception of buspirone, all first indication anxiolytics were introduced before 1975, before many of the modern techniques of medicinal chemistry such as radioligand binding assays, molecular modeling, and pharmacokinetic screening were introduced into common practice. 

Needham, S.R. Cole, M.J. Fouda, H.G. Direct Plasma Injection for High-Performance Liquid Chromatographic-Mass Spectrometric Quantitation of the Anxiolytic Agent CP-93393, J. Chromatogr. B 718, 87-94 (1998). 

The anxiolytic agents consist of benzodiazepine derivatives and azaspirodecanedione derivatives. For a long period of... 

There is also a report on a novel approach to the anxiolytic agents buspirone and gepirone [93H(36)1463]. 2,4-Diaminopyrimidines of type 39 have been prepared starting from alkyl and benzyl ketones (37) [94H(38)37S]. 

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