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PubMed1998

Identification of the domains of photoincorporation of the 3'- and 7-benzophenone analogues of taxol in the carboxyl-terminal half of murine mdr1b P-glycoprotein.

P-glycoprotein is an ATP-dependent drug-efflux pump that can transport a diverse range of structurally and functionally unrelated hydrophobic compounds across the plasma membrane. The transporter is composed of two homologous halves, each containing a nucleotide binding fold and six putative transmembrane spanning segments. The contact domains between the murine mdr1b P-glycoprotein and two photoreactive Taxol analogues have been mapped by a combination of CNBr digestion and immunoprecipitation studies. We had demonstrated previously that the 3'-p-benzoyldihydrocinnamoyl (BzDC) analogue of Taxol specifically photolabeled mdr1b P-glycoprotein and now show that the corresponding C-7 analogue likewise specifically photoincorporates into the transporter. CNBr digestion of both photolabeled P-glycoproteins gave rise to an approximate 10 kDa tritium-labeled peptide, each of which was a distinct polypeptide. The CNBr fragment generated from the 3'-BzDC-Taxol-photolabeled P-glycoprotein was immunoprecipitated by a polyclonal antibody (Ab7) raised against amino acid residues 1008-1019 of the mdr1b isoform. In contrast, the CNBr fragment generated from the 7-BzDC-Taxol-photolabeled P-glycoprotein was immunoprecipitated by a polyclonal antibody (Ab4) raised against amino acid residues 740-750. The specificity of these reactions was demonstrated by showing that the presence of the appropriate synthetic peptide blocked the immunoprecipitation. Moreover when the antibodies were reversed, no immunoprecipitation occurred. Based on the deduced amino acid sequence of mdr1b P-glycoprotein, and its hydropathy plot analysis, our data indicated that the 3'-BzDC group photoincorporates into amino acid residues 985-1088, a region of the transporter that includes half of TM 12 and terminates just after the Walker A motif in the second nucleotide binding fold. The 7-BzDC group photoincorporates into amino acid residues 683-760, a region of the transporter that includes all of TM 7 and half of TM 8 plus the intervening extracellular loop.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Characterization of two taxol photoaffinity analogues bearing azide and benzophenone-related photoreactive substituents in the A-ring side chain.

Taxol is a structurally novel and clinically effective antitumor drug, which, unlike other antimitotic agents, induces the assembly of tubulin into microtubules. To characterize the binding site(s) of taxol on the microtubule, taxol-based photoaffinity reagents 1 and 2 bearing photoreactive groups on the A-ring side chain were prepared and evaluated. Taxol analogue 1 exhibits better microtubule assembly activity, greater cytotoxicity toward J774.2 cells, and more specific and efficient photolabeling of the beta-subunit of tubulin than does analogue 2. Therefore, it would appear that 1 is the better candidate for further studies aimed at the characterization of the taxol binding site on the microtubule.

Affinity Labels↗
PubMed2003

Three-fold interpenetrating three-dimensional networks based on C-methylcalix[4]resorcinarene incorporating benzophenone guest molecules.

A new solid based on C-methylcalix[4]resorcinarene and the linker molecule bis(4-pyridylmethylidyne)hydrazine (bpmh) has been prepared, in which brick-wall sheets are linked in the third dimension to give networks with three intersecting perpendicular channels; the networks interpenetrate three-fold, but nevertheless leave cavities capable of including sizable guest molecules.

Journal Article↗
PubMed1999

Characterization of the Taxol binding site on the microtubule. Identification of Arg(282) in beta-tubulin as the site of photoincorporation of a 7-benzophenone analogue of Taxol.

Photoaffinity labeling methods have allowed a definition of the sites of interaction between Taxol and its cellular target, the microtubule, specifically beta-tubulin. Our previous studies have indicated that [(3)H]3'-(p-azidobenzamido)Taxol photolabels the N-terminal 31 amino acids of beta-tubulin (Rao, S., Krauss, N. E., Heerding, J. M., Swindell, C. S., Ringel, I., Orr, G. A., and Horwitz, S. B. (1994) J. Biol. Chem. 269, 3132-3134) and [(3)H]2-(m-azidobenzoyl)Taxol photolabels a peptide containing amino acid residues 217-233 of beta-tubulin (Rao, S., Orr, G. A., Chaudhary, A. G., Kingston, D. G. I., and Horwitz, S. B. (1995) J. Biol. Chem. 270, 20235-20238). The site of photoincorporation of a third photoaffinity analogue of Taxol, [(3)H]7-(benzoyldihydrocinnamoyl) Taxol, has been determined. This analogue stabilizes microtubules polymerized in the presence of GTP, but in contrast to Taxol, does not by itself enhance the polymerization of tubulin to its polymer form. CNBr digestion of [(3)H]7-(benzoyldihydrocinnamoyl)Taxol-labeled tubulin, with further arginine-specific cleavage by clostripain resulted in the isolation of a peptide containing amino acid residues 277-293. Amino acid sequence analysis indicated that the photoaffinity analogue cross-links to Arg(282) in beta-tubulin. Advances made by electron crystallography in understanding the structure of the tubulin dimer have allowed us to visualize the three sites of photoincorporation by molecular modeling. There is good agreement between the binding site of Taxol in beta-tubulin as determined by photoaffinity labeling and electron crystallography.

Animals↗
PubMed1986

Intestinal activation of a new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative, in rats.

5-[(2- Aminoacetamide)methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl]- N,N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S) is a newly synthesized sleep inducer, which itself has negligible affinities for benzodiazepine receptors. However, several active metabolites have been found in rat plasma. In this paper, the mechanisms and contribution of the activation of 450191-S in rat small intestine were investigated. When 450191-S was incubated with rat everted small intestine, desglycylated 450191-S (191 DG) was released in the medium and subsequently converted to 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-1). The results obtained using synthetic 191DG indicated that the conversion of 191DG to M-1 was spontaneous and very rapid, with a half-life of 9 min in pH 7.4 buffer. After incubation, the intestinal tissue contained a small amount of unchanged 450191-S but large amounts of 191DG and/or M-1. Next, metabolites in the mesenteric blood were determined following instillation of 14C-450191-S into a segment of rat ileum and it was found that almost all of the radioactivity in the blood was accounted for by 191DG and/or M-1. In conclusion, 450191-S is metabolized by intestinal aminopeptidases to 191DG, which is spontaneously converted to M-1, an active metabolite, and the activation is completed by a single passage through the intestinal wall.

Aminopeptidases↗
PubMed1986

Effect of food on absorption of 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative from rat small intestine.

5-[(2-Aminoacetamide)methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl]- N, N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a newly synthesized sleep inducer, is a masked compound which is converted to 1,4-benzodiazepine by intestinal aminopeptidases during absorption from the small intestine. This study was an investigation on the effects of food on 450191-S pharmacokinetics. When 14C-450191-S was administered to non-fasted rats, peak plasma levels of total radioactivity were markedly reduced and its excretion into the bile was more delayed than when it was administered to fasted rats. One of the causes for these phenomena was thought to be a delayed absorption caused by the direct interaction between 450191-S and food in the intestinal lumen as well as the delayed gastric emptying rate. To confirm this interaction, we examined the effect of food on 450191-S uptake by the small intestine using rat everted jejunal sac in vitro. Subsequently, we found that the desglycylation of 450191-S was inhibited by rat food and that the uptake of 450191-S was reduced. In conclusion, 450191-S absorption is delayed by food, which results in the decreased total plasma level of 450191-S metabolites.

Administration, Oral↗
PubMed1986

Uptake of 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative, in the everted sac of rat small intestine: role of intestinal aminopeptidases.

5-[(2-Aminoacetamido)methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl ]-N,N-dimethyl-1 H-1,2,4-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a sleep inducer, is a ring-opened derivative of 1,4-benzodiazepine and has been reported to be activated by intestinal aminopeptidases in a step of absorption. In this study, we investigated the role of the intestinal aminopeptidases in the uptake of 450191-S by the intestine by using various aminopeptidase inhibitors in everted sacs of rat small intestine in vitro. Glycylglycine did not affect the desglycylation of 450191-S but glycyl-L-leucine or L-leucyl-L-leucine inhibited the reaction. This inhibition was accompanied by reduced concentration of 450191-S metabolites in the intestinal tissue. When the incubation was carried out at 0 degrees C or with puromycin, the desglycylation was also inhibited and the concentration was similarly reduced. Since the extent of inhibition of the desglycylation of 450191-S was negatively correlated with the total concentration of 450191-S metabolites in the intestinal tissue (r = 0.9660), the aminopeptidases must play an important role in the uptake of 450191-S by the intestine. To confirm this, we examined the uptake of the desglycylated product of 450191-S, 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo- [1,5-alpha] [1,4]-benzodiazepine-2-carboxamide (M-1) in the same manner. No effect of dipeptides, puromycin or reduced temperature was found on M-1 uptake by the intestine, leading to the conclusion that the aminopeptidases are important for enhancing the uptake of 450191-S in the intestine.

Aminopeptidases↗
PubMed1986

Autoinduction of 450191-S, a new sleep inducer of 1H-1,2,4-triazolyl benzophenone derivative, in dogs.

Alterations of plasma metabolite profiles were studied following single or multiple oral administrations of 5-[(2-aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl]-N, N-dimethyl-1H-1, 2,4-triazole-3-carboxamide hydrochloride dihydrate (450191-S) in Beagle dogs. In plasma, unchanged 450191-S was not detected, but active metabolite, 8-chloro-6-(2-chlorophenyl)-2-(N, N-dimethylcarbamoyl)-4H-1,2, 4-triazolo [1, 5-a] [1, 4] benzodiazepine (M-1) appeared first, followed by four active metabolites that were hydroxylated or demethylated in the N, N-dimethylcarbamoyl side chain of M-1. At single doses of 5 to 50 mg/kg, the areas under the plasma concentration-time curves (AUCs) of the metabolites were linearly increased, showing that there was no saturable process in the steps of absorption, distribution, metabolism and excretion. After multiple administrations (50 mg/kg/d for 15 d), the same metabolites appeared in the plasma but the patterns of the plasma metabolite profiles were considerably different from those after single administrations. The peak plasma levels of M-1 and its hydroxylated metabolites in the carbamoyl side chain were attained more rapidly in the multiple administrations, demonstrating higher peak values compared to those in the single administrations, and the eliminations of these metabolites from plasma were also rapid. However, no difference in the values of the AUCs were observed between single and multiple administrations. With the other active metabolites, the peak plasma levels after multiple administrations were considerably lowered by rapid elimination, resulting in a marked increase in AUCs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

[Effect of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivative 450191-S on rat liver drug-metabolizing enzyme system].

The effect of a new sleep inducer, 450191-S, on the hepatic drug-metabolizing enzyme system was examined using rats and compared with those of nitrazepam and phenobarbital. Cytochrome P-450-dependent 7-alkoxycoumarin O-dealkylation activity determined using liver homogenate and isolated microsomes increased after successive oral administrations of 450191-S, and induction of the enzyme system was observed by administration of 150 approximately 200 mg/kg of the drug for at least 3 approximately 5 days. Normal activity was recovered with withdrawal of the drug for 3 approximately 5 days after induction of the hepatic enzyme system. Administration of higher amounts of 450191-S (200 approximately 600 mg/kg/day) for 3 days caused remarkable increases in the O-dealkylase and UDPGA-glucuronyltransferase activities and cytochrome P-450 and b5 contents. Similar changes in the hepatic enzyme system were observed with administration of nitrazepam (200 approximately 600 mg/kg for 3 days, p.o.) or phenobarbital (10 approximately 40 mg/kg for 3 days, i.p.). We concluded that the inducing activity of 450191-S is almost the same as that of nitrazepam, but weaker than that of phenobarbital. When the hepatic enzyme system was induced by the administration of either 450191-S or phenobarbital, the pentobarbital-induced sleeping time was shortened with increasing doses of the drugs. On the other hand, sleeping time was prolonged by the administration of another type of inducer, beta-naphthoflavone. The results suggest that the inductive pattern of 450191-S is similar to that of phenobarbital.

Animals↗
PubMed1985

[Transport of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative (450191-S), and its active metabolites to the brain in rats and mice].

The transport of a new sleep-inducer, 450191-S, and its metabolites, M-1, M-2, M-A, M-3 and M-4, to the brain was examined by the BUI (Brain Uptake Index) method in rats and by comparing the plasma and the brain concentration of the metabolites in mice. 450191-S was not passed to the brain and M-A was hardly passed, but the permeability of M-1, M-2 and M-3 was as high as that of diazepam. The blood-brain barrier (BBB) permeability of these benzodiazepines correlated with the lipid solubility expressed by the Rm value. After oral administration of 450191-S or M-1 to mice, the common major metabolites, M-1, M-2, M-A, M-3 and M-4, were detected in the plasma. At the dose level of 5.5 mumol/kg, M-A showed the highest plasma concentration among the metabolites, but only a low level in the brain. At an increased dose of 55 mumol/kg, M-2 showed the highest concentration in both the plasma and the brain. These results with mice correlated well with the results of BBB permeability in rats. The brain level of M-4 was almost at the background level in spite of a considerable plasma level. The total brain concentration of pharmacologically active metabolites immediately after administration of M-1 rose much faster and to a higher level than after 450191-S administration. These results may explain the pharmacological character of 450191-S.

Animals↗
PubMed1986

[Pharmacology of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (VI). Determination of metabolites in monkey plasma by combined high-performance liquid chromatography and enzyme immunoassay].

A new sleep-inducer, 450191-S, was orally administered to two old rhesus monkeys and three young ones at a pharmacologically active dose (1 mg/kg). The area under the plasma concentration versus time curve (AUC) of M-1 was the smallest among the measured metabolites. The AUC of M-2 in the old monkeys was 10 times higher than that of the young ones. M-A was one of the major metabolites, and its AUC in the old monkeys was also four times higher than that in the young ones. The AUC of M-3 was the largest among the measured metabolites. The time of maximum concentration was 12-16 hr after dosing; and thereafter, the concentration decreased gradually with a 12-hr half-life. The M-4 level was constantly low during 24 hr after dosing and then decreased gradually. The active metabolite M-1 was also administered to the two young monkeys at a dose of 0.73 mg/kg, and the time course of the plasma concentration of metabolites was compared with that after 450191-S administration to the young monkeys, because 450191-S may be changed to M-1 in the process of intestinal absorption. The concentration of M-1 was extremely low in spite of the dosing of M-1 itself, and the AUC of M-1 was one-sixth of that after 450191-S administration. The concentration of M-2 was also low, and its AUC was one-third of that after 450191-S administration. The AUC's of M-A, M-3 and M-4 were not very different from those after 450191-S administration. These results indicated that there is an age-related difference in the plasma concentration of M-2 and M-A when 450191-S is administered orally and that the plasma concentrations of M-1 and M-2 differ greatly between 450191-S and M-1 administrations.

Administration, Oral↗
PubMed1987

[Pharmacological studies of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivatives (450191-S, rilmazafone hydrochloride) (VII). Comparison of sleep-inducing activities between young and elderly rhesus monkeys].

The sleep-inducing activities of 450191-S (rilmazafone hydrochloride) were compared among two groups of elderly and one group of young rhesus monkeys, and the relationship between blood levels of five active metabolites of 450191-S and sleep-inducing activities was also examined. Oral administration of 450191-S, 1 mg/kg, caused the quick appearance of slow wave deep sleep (SWDS) and its stable continuity in elderly monkeys, and no significant differences in various sleep parameters were observed among the two groups of eight elderly monkeys. An increase of SWDS was always accompanied by a high blood level of active metabolite M-2. On the other hand, in the young rhesus monkey group, the amount of SWDS and its mean continuity were significantly less, and differences were evident in sleep parameters obtained from a nocturnal 14 hr observation. In conclusion, the difference of sleep-inducing activities between elderly and young monkeys seem to be caused by a difference in the blood level of active metabolites of 450191-S, particularly M-2.

Age Factors↗