The influence of sulfur substituents on the molecular geometry and packing of thio derivatives of N-methylphenobarbital.

The room-temperature crystal structures of four new thio derivatives of N-methylphenobarbital [systematic name: 5-ethyl-1-methyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione], C(13)H(14)N(2)O(3), are compared with the structure of the parent compound. The sulfur substituents in N-methyl-2-thiophenobarbital [5-ethyl-1-methyl-5-phenyl-2-thioxo-1,2-dihydropyrimidine-4,6(3H,5H)-dione], C(13)H(14)N(2)O(2)S, N-methyl-4-thiophenobarbital [5-ethyl-1-methyl-5-phenyl-4-thioxo-3,4-dihydropyrimidine-2,6(1H,5H)-dione], C(13)H(14)N(2)O(2)S, and N-methyl-2,4,6-trithiophenobarbital [5-ethyl-1-methyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trithione], C(13)H(14)N(2)S(3), preserve the heterocyclic ring puckering observed for N-methylphenobarbital (a half-chair conformation), whereas in N-methyl-2,4-dithiophenobarbital [5-ethyl-1-methyl-5-phenyl-2,4-dithioxo-1,2,3,4-tetrahydropyrimidine-6(5H)-one], C(13)H(14)N(2)OS(2), significant flattening of the ring was detected. The number and positions of the sulfur substituents influence the packing and hydrogen-bonding patterns of the derivatives. In the cases of the 2-thio, 4-thio and 2,4,6-trithio derivatives, there is a preference for the formation of a ring motif of the R(2)(2)(8) type, which is also a characteristic of N-methylphenobarbital, whereas a C(6) chain forms in the 2,4-dithio derivative. The preferences for hydrogen-bond formation, which follow the sequence of acceptor position 4 > 2 > 6, confirm the differences in the nucleophilic properties of the C atoms of the heterocyclic ring and are consistent with the course of N-methylphenobarbital thionation reactions.

Binding site location on GABAA receptors determines whether mixtures of intravenous general anaesthetics interact synergistically or additively in vivo.

BACKGROUND AND PURPOSE: General anaesthetics can act on synaptic GABAA receptors by binding to one of three classes of general anaesthetic sites. Canonical drugs that bind selectively to only one class of site are etomidate, alphaxalone, and the mephobarbital derivative, R-mTFD-MPAB. We tested the hypothesis that the general anaesthetic potencies of mixtures of such site-selective agents binding to the same or to different sites would combine additively or synergistically respectively. EXPERIMENTAL APPROACH: The potency of general anaesthetics individually or in combinations to cause loss of righting reflexes in tadpoles was determined, and the results were analysed using isobolographic methods. KEY RESULTS: The potencies of combinations of two or three site-selective anaesthetics that all acted on a single class of site were strictly additive, regardless of which single site was involved. Combinations of two or three site-selective anaesthetics that all bound selectively to different sites always interacted synergistically. The strength of the synergy increased with the number of separate sites involved such that the percentage of each agent's EC50 required to cause anaesthesia was just 35% and 14% for two or three sites respectively. Propofol, which binds non-selectively to the etomidate and R-mTFD-MPAB sites, interacted synergistically with each of these agents. CONCLUSIONS AND IMPLICATIONS: The established pharmacology of the three anaesthetic binding sites on synaptic GABAA receptors was sufficient to predict whether a mixture of anaesthetics interacted additively or synergistically to cause loss of righting reflexes in vivo. The principles established here have implications for clinical practice.

Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation.

The 8-hour urinary recovery of 4-hydroxy-mephobarbital has been measured after oral administration of racemic mephobarbital (90 mg) in 17 extensive (EM) and six poor (PM) metabolizer phenotypes of mephenytoin. The recovery of this metabolite was measurable in every EM and ranged from 2.5% to 48% (10.9% +/- 1.9% of dose), but was not detected in any PM (less than 1% of dose). In EMs, the 8-hour urine recovery of 4-OH-mephobarbital after mephobarbital was approximately half that of 4-OH-mephenytoin over the same time after mephenytoin administration. One EM received similar doses of R- and S-mephobarbital on separate occasions. Urinary recovery of 4-OH-mephobarbital was 33% and less than 1%, respectively. These results suggest that mephobarbital is stereoselectively hydroxylated by the same drug metabolizing enzyme that is responsible for the stereoselective aromatic hydroxylation of mephenytoin.

Synthesis of N-beta-D-glucopyranosyl derivatives of barbital, phenobarbital, metharbital, and mephobarbital.

The condensation of per(trimethyl)silylbarbital and -phenobarbital with 1,2,3,4,6-penta-O-acetyl-beta-D-glucopyranose in the presence of stannic chloride in dichloroethane gave moderate yields of the beta-coupled barbiturate N-D-glucopyranosyl derivatives. Reaction of metharbital and mephobarbital under the same conditions was unsuccessful. The homologous N-methylglucosides were prepared by reaction of the barbital and phenobarbital N-glucosyl derivatives with diazomethane. The diastereomers of the phenobarbital and mephobarbital derivatives were resolved by use of C-18 reverse-phase h.p.l.c. 1H- and 13C-n.m.r. spectroscopy, and thermospray 1.c.-m.s. proved to be the most useful methods for characterizing the barbiturate glucosides.

Synthesis of N-beta-D-glucopyranosyluronate derivatives of barbital, phenobarbital, metharbital, and mephobarbital.

The synthesis and characterization of barbital, phenobarbital, metharbital, and mephobarbital glucuronides is reported. The condensation of per(trimethylsilyl)-barbital and -phenobarbital with methyl 1,2,3,4-tetra-O-acetyl-beta-D-glucopyranuronate in the presence of trimethylsilyl trifluoromethanesulfonate gave moderate yields of the N1-(beta-D-glucopyranosyluronate) barbiturate derivatives. The diastereomers of the phenobarbital derivatives were resolved by use of C18 reversed-phase HPLC. The homologous N3-methyl barbiturate N1-glucuronates were prepared by reaction of the barbital and phenobarbital N1-glucuronate derivatives with diazomethane. The absolute configuration of the phenobarbital N1-beta-D-glucopyranuronate epimers was determined by oxidative removal of the glycon from the mephobarbital N1-beta-D-glucopyranuronate epimers to give the optical isomers of mephobarbital. The spectroscopic data for this series of compounds will facilitate the characterization of N-glycosylated imide xenobiotics that may be detected as mammalian metabolites in biodisposition studies.

[Morphological changes in the liver of rats treated with phenobarbital, methylphenobarbital and their N-substituted morpholinoethyl derivatives]. / Morfologichni promeni v cherniia drob na tretirani plakhove s fenobarbital, metil fenobarbital i tekhnite N-substituirani merfolinoetilni proizvodni.

The authors carried out histologic and electrone microscopic studies of liver in rats, treated with phenobarbital, methylphenobarbital, with their N-substituted morpholinoethye derivatives as well as in rats from the control group of animals. It was established that phenobarbital and methylphenobarbital caused hypertrophy and vacuolization of endoplasmatic reticulum, but the first preparation of the myelin degeneration of mitochindria as well. Morpholinethyl derivatives of the mentioned two compounds induced above all activation of lysosomes as well as reaction of Goldgi apparatus in the parenchymatous cells of liver. The observed ultrastructural changes were connected with differences in the induced drug-metabolizing enzymic properties of the two groups of compounds, established by the authors in their previous studies.