Structure-activity relationships barbiturates

Barbiturates structure-activity relationships 60 Metabolism of barbiturates 60... 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Klopman, G. and Raychaudhury, C. (1990). Vertex Indices of Molecular Graphs in Structure-Activity Relationships A Study of the Convulsant-Anticonvulsant Activity of Barbiturates and the Carcinogenicity of Unsubstituted Polycyclic Aromatic Hydrocarbons. J. Chem. Inf ComputSci.,30,12-19. 

Hansch, C., Anderson, S. M. The structure—activity relationship in barbiturates and its similarity to that in other narcotics. J. Med. Chem. 1967,10, 745-753. 

Mopman, G. and Raychaudhury C. (1990) Vertex indices of molecular graphs in structure-activity relationships a study of the convulsant— anticonvulsant activity of barbiturates and the carcinogenicity of unsubstituted polycyclic aromatic hydrocarbons. /. Chem. Inf. Comput. Sci., 30, 12-19. 

More details on synthesis, properties, and reactivity are provided in the review byLevinaandV elichko in 1960.4 Since that time further studies dealing with structure and conformation, spectral properties, and structure-activity relationships have been among the main advances in barbiturate chemistry. These topics were reviewed by Bobranski.5 This review presents the most important recent information on barbituric acids with special emphasis on their physicochemical properties. 

Figure 12-11. Empirical structure-activity relationships of barbiturants.

Barbituric acid itself does not possess any hypnotic properties. It is only when the two active hydrogen atoms at position 5 5 have the appropriate substituent e.g., alkyl or aryl groups) that the hypnotic activity is produced by the compound. The following cardinal points must be taken into consideration with respect to the structure-activity relationship amongst the barbiturates. These are ... 

A structure-activity relationship of sixty-two steroids as hypnotic agents, and the observation that a few Sor and SP pregnane derivatives were more potent than barbiturates when given intravenously in nonaqueous solvents, was published. Epipregnanolone (23) had a minimal anesthetic dose of 2.5 mg/kg in the mouse. 

Hansch and coworkers, in their continuing attempts to place the discussion of structure-activity relationships of biologically active compounds on a mathematic basis, have presented evidence that the hypnotic activity of groups of barbiturates depends almost entirely on their relative lipophilic character as defined by their octanol-water partition coefficients. Although hypnotic activity was the model, the principle should apply to other actions of drugs in the central nervous system. 

M. Cuenca Benito, S. Sagrado, R.M. Villanueva Camanas and M.J. Medina Hernandez, Quantitative Retention-Structure and Retention-Activity Relationships of Barbiturates by MLC, J. Chromatogr. A, 814 121 (1998). 

Tong and Lien reported significant correlation between the inhibition of beef-heart submitochondrial NADH oxidation by 14 barbiturates and their corn oil-water partition coefficient. However, when the data for stimulation of rat liver microsomal NADPH oxidation by the same barbiturates were correlated, a good correlation was observed only after exclusion of 5-allylbarbiturates, which indicates different activity of the allyl group in this biotransformation process.542 The relationship between molecular structure and duration of depressant effect for 160 5,5-disubstituted barbiturates was investigated by the so-called Pattern Recognition Technique. The results were consistent with those obtained via the Hansch approach.543... 

---