Barbiturates fundamentals

The fundamental neurobiological importance of the GABA A receptor is underscored by observations that even more receptor sites exist at or near this complex (Fig. 8—20). This includes receptor sites for nonbenzodiazepine sedative-hypnotics such as zolpidem and zaleplon, for the convulsant drug picrotoxin, for the anticonvulsant barbiturates, and perhaps even for alcohol. This receptor complex is hypothetically responsible in part for mediating such wide-ranging CNS activities as seizures, anticonvulsant drug effects, and the behavioral effects of alcohol, as well as the known anxiolytic, sedative-hypnotic, and muscle relaxant effects of the benzodiazepines. 

The mechanism of retention on chiral phases that is based on multiple hydrogen bonding formation involves the formation of base pairs and triple hydrogen bonds between the solutes and the chiral stationary phase 95 Fundamental work in this area has been done by Hara and Dobashi,96 97 using amino acid amide and tartaric acid amide phases. In addition, N,N -2,6-pyridinediyl bis(alkanamides) chemically bonded to silica gel have been described for the resolution of barbiturates 95... 

Several earlier review articles are cited in the fundamental work of Doran in 1959.3 This book provides general information on the chemistry and pharmacology of barbiturates, but its main value lies in a compilation of an extensive bibliography on the preparation and pharmacological activity of these compounds. 

Hundreds of barbiturates have been synthesized on a trial-and-error basis. Although many structural features required for hypnotic activity have been recorded, no clear correlation between structure and activity has emerged. In 1951, Sandberg (43) made his fundamental postulation that to possess good hypnotic activity, a barbituric acid must be a weak acid and must have a lipid/water partition coefficient between certain limits. Therefore, only the 5,5,-disubstituted barbituric acids, the 5,5,-disubstituted thiobarbituric acids, and the 1,5,5-trisubstituted barbituric acids possess acceptable hypnotic, anticonvulsant, or anesthetic activity. All other substitution patterns, such as 5-monosubstituted barbituric acids, 1,3-disubstituted barbituric acids, or 1,3,5,5-tetrasubstituted barbituric acids, are inactive or produce convulsions. 

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