(3SR,4aRS,6SR,8aRS)-6-(1H-tetrazol-5-yl)decahydroisoquinoline-3-carboxylic acid, a novel, competitive, systemically active NMDA and AMPA receptor antagonist

We report the synthesis and characterization of 6 (LY246492), which is a competitive N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptor antagonist. Tetrazole-substituted amino acid 6 was prepared in four steps from the recently described aldehyde 7. The optical isomers (-)-6 and (+)-6 were obtained from the same sequence of reactions using the corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of responses mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.     

Stereoselective differences in the vasorelaxing effects of S(+) and R(-) ketamine on rat isolated aorta

BACKGROUND: S(+) ketamine, because of its higher anesthetic potency and lower risk of psychotomimetic reactions, has been suggested to be superior to presently available racemic ketamine. The racemate is a direct vasodilator in vivo, and thus the authors investigated the vasorelaxing effects of ketamine enantiomers on rat aorta. METHODS: Rat isolated aortic rings with and without endothelium were contracted with 3 x 10(-7) M norepinephrine. Then 10(-5) to 3 x 10(-3) M S(+), R(-), or racemic ketamine were added cumulatively. Vascular responses to ketamine were further studied in rings pretreated with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (NNLA), the adenosine triphosphate-sensitive K+ channel antagonist glibenclamide, and the L-type calcium channel blocking agent D888. RESULTS: Ketamine enantiomers and the racemate produced concentration-dependent vasorelaxation. The relaxing effect of S(+) ketamine was significantly weaker compared with R(-) ketamine and the racemate reflected by the half-maximum effective concentration (EC50) values of 11.6 x 10(-4), 4.8 x 10(-4), and 6 x 10(-4) M, respectively. Removal of the endothelium and NNLA or glibenclamide pretreatment did not significantly alter the vasorelaxing effect of ketamine. In contrast, D888 pretreatment significantly shifted the concentration-effect curves of both S(+) and R(-) ketamine rightward (EC50 values of 18.9 x 10(-4) and 8.5 x 10(-4) M, respectively), whereas the difference between the isomers was not affected. CONCLUSIONS: Vasorelaxation by ketamine enantiomers is quantitatively stereoselective: The effect of S(+)ketamine is significantly weaker compared with that of the racemate and R(-) ketamine. This stereoselective difference is not due to nitric oxide release, activation of adenosine triphosphate-sensitive potassium channels, or differential inhibition of L-type calcium channels.     

(-)-3-Isothujone, a small nonnitrogenous molecule with antinociceptive activity in mice

(-)-3-Isothujone and (+)-3-thujone were examined for antinociceptive activity using the hot-plate and Nilsen tests. In the hot plate test (-)-3-isothujone (ED50 = 6.5 mg/kg) was found to be codeine-like and equipotent with (-)-delta9-tetrahydrocannabinol while the racemic material was essentially half as potent as the levoratatory isomer. (+)-3-Thujone was inactive in both antinociceptive tests as were several structural analogues of the 3-thujones. As with the THC's less antinociceptive activity was observed in the Nilsen test than in the hot-plate assay. Acute toxicities for the 3-thujones were determined and vastly improved synthetic procedures have been developed for two long-known but difficulty accessible 3-thujanols.     

(3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: a conformationally restricted analogue of the NR2B subtype-selective NMDA antagonist (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)- 1-propanol

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptor-cis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1- yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.     

Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients

KE-298 is a new immunomodulatory agent with a chemical structure similar to that of D-penicillamine. We compared the effects of KE-298 on type II collagen-induced arthritis (CIA) in mice with those of prednisolone. KE-298 at a dose of 25 mg/kg showed only a decrease in the progression of foot pad swelling. At doses of 50 and 100 mg/kg, however, KE-298 inhibited the severity and development of the collagen-induced arthritis index, the progression of foot pad swelling, bone damage and histopathological changes. These inhibitory effects were more pronounced at the dose of 50 mg/kg than at 100 mg/kg. KE-298 also significantly inhibited the delayed-type hypersensitivity (DTH) response to type II collagen, but did not affect the production of anti-type II collagen IgG antibody in arthritic mice. To determine the inhibitory mechanism of KE-298, we studied the effect of KE-298 on IL-1 beta and TNF-alpha production in mice. We found that KE-298 inhibited bacterial lipopolysaccharide (LPS)-induced IL-1 beta production at doses of 50 and 100 mg/kg. It inhibited the production of TNF-alpha at the dose of 50 mg/kg, but not at 100 mg/kg. In summary, at appropriate dosages, KE-298 inhibited CIA and TNF-alpha production in mice. KE-298 also inhibited the DTH reaction to type II collagen and LPS-induced IL-1 beta production in a dose-related fashion. These findings suggest that these effects of KE-298 are closely related to its immunomodulatory action.     

Effects of configuration on the myocardial uptake of radioiodinated 3(R)-BMIPP and 3(S)-BMIPP in rats

Radioiodinated 3(R)-(+)- and 3(S)-(-)-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) were prepared and evaluated in rats to investigate the effects of absolute configuration of the 3(beta)-methyl group on myocardial uptake and release kinetics. METHODS: The 3(R)-(+)-BMIPP analog was synthesized by initial acylation of a thiophene template with the acid chloride of ethyl 3(R)-methylglutarate. 3(S)-(-)-BMIPP was obtained by separation from the mixture of diastereomeric amides prepared from reaction of the acid chloride of racemic BMIPP with the S-(-)-alpha-methylbenzylamine. The amide of synthetic 3(R)-BMIPP prepared from S-(-)-alpha-methylbenzylamine was identical to the chromatographically more polar isomer. Free acids were obtained by acid hydrolysis of the amides, fully characterized and then converted to the radioiodinated BMIPP isomers. RESULTS: Biodistribution studies in rats with the dual-labeled [(131)I]-3(S)-BMIPP/[(125)I]-3(R)-BMIPP mixture demonstrated greater myocardial uptake of 3(R)-BMIPP compared with the 3(S)-BMIPP isomer [60 min: 3(R)-BMIPP = 4.37 %ID/g; 3(S)-BMIPP = 3.44; p < 0.05; 180 min, 2.31 and 1.78 %ID/G, respectively, p < 0.01], although both isomers had similar myocardial washout curves (5-180 min). Percent ID/g values for other tissues which were examined (blood, lungs, thyroid) were similar. CONCLUSION: Higher myocardial uptake of the 3(R)-BMIPP isomer observed in these animal studies may suggest differences in carrier-mediated myocyte uptake of the two isomers. These studies suggest that [(123)I]-3(R)-BMIPP is a candidate for clinical evaluation and may show greater myocardial uptake than the 3(S)-BMIPP isomer and may thus require reduced injected dose.     

Isomers of erythro-5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril, a new bronchodilator

The isomers of erythro-5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril (1), a new potent and beta2-selective bronchodilator, were synthesized by optical resolution of compound 1 and inversion of the erythro to the threo isomers. The isomers were tested for activities to inhibit histamine-induced bronchospasm and to increase the heart rate of anesthetized dogs. Racemic and (-)-erythro-1 showed potent and beta2-selective bronchodilater activities. Among the isomers, (-)-erythro-1 showed the highest activities and (+)-erythro-1 showed the lowest.     

Methcathione ("cat"): an enantiomeric potency comparison

With regard to its chemical structure, methcathinone is to cathinone what methamphetamine is to amphetamine. Although it is a drug of abuse outside the United States, methcathione is only recently making an appearance on the clandestine market in this country and has just been classified a Schedule I substance under the Emergency Scheduling Act. We have previously demonstrated that racemic methcathinone produces locomotor stimulation in mice, and substitutes for cocaine and (+)amphetamine in rats trained to discriminate either cocaine or (+)amphetamine, respectively, from saline in tests of stimulus generalization. Because an enantiomeric potency comparison has never been reported for the optical isomers of methcathinone, in the present investigation we synthesized samples of S(-)- and R(+)methcathinone and compared them for their ability: a) to produce locomotor stimulation in mice, b) to elicit cocaine-like responding in rats trained to discriminate 8.0 mg/kg of cocaine from saline vehicle, and c) to elicit (+)-amphetamine-appropriate responding in rats trained to discriminate 1.0 mg/kg of (+)amphetamine from saline vehicle. S(-)Methcathinone was about twice as potent as S(+)amphetamine and three to five times more potent than R(+)methcathinone in the three pharmacologic assays. We conclude that both optical isomers possess central stimulant character, but that S(-)methcathinone is somewhat more potent than R(+)methcathinone.     

Preliminary toxicokinetic study with different crystal forms of S (+)-ibuprofen (dexibuprofen) and R,S-ibuprofen in rats

The aim of the study was to gain information on the plasma concentration-time profiles of both ibuprofen (CAS 15687-27-1) enantiomers in the rat after single oral application of two different crystal forms of S (+)-ibuprofen (dexibrufen, CAS 51146-56-6) and racemic ibuprofen in order to optimize blood-sampling times in a subsequent subchronic toxicity study. The application of either commercial racemic ibuprofen or recrystallised S (+)-ibuprofen (60 mg/kg) to two groups of 4 rats per blood sampling term was carried out in order to define Cmax and tmax and AUC of the plasma-concentrations of the ibuprofen enantiomers. The crystals of commercial (manufactured according to an usual manufacturing procedure) and recrystallised (S(+)- and racemic ibuprofen were different in respect to their shape and size. The recrystallised crystal species of S (+)- and racemic ibuprofen has better galenic (tabletting-) properties and tablets containing the modified S (+)-ibuprofen species showed favorable clinical results. The toxicokinetic behaviour of the recrystallised species was investigated in comparison to the commercial crystal species because of its slightly but significantly slower dissolution rate in simulated gastric and enteric juice. As the AUC0-24 h S-(+)-ibuprofen and the AUC0-24 h, R-(-)-ibuprofen after application of commercial and recrystallised crystal species were not different, the crystal form apparently did not exert an influence on the extent of absorption of S-(+)-ibuprofen and racemic ibuprofen in the rat. The rat has a high inversion capacity and the inversion of R-(-)-ibuprofen after application of commercial and recrystallised racemic ibuprofen was nearly complete in this study. The effects of crystallinity on solubility in simulated media in vitro did not correlate to the findings on the extent of absorption in the rat in vivo.     

Comparative findings on the stereoselectivity of cholinoreceptors

The potency of the optical isomers of the muscarinomimetic agent 2-methyl-4-dimethylaminomethyl-1.3-dioxolane methiodide (F-2268) was compared on cholinoreceptors, (ChR) of different animals. The greatest difference between optical isomers was observed on the muscarinic ChR of guinea pig ileum smooth muscle cis-L(+)isomer being more than hundred times as potent as cis-D(-)isomer. On the ChR of muscarinic type in the holothuria Cucumaria japonica retractor muscle, cis-L(+)isomer was 25 times as efficient as cis-D(-)isomer. On the ChR of sea urchin and sipunculid locomotor muscles, optical isomers differ only 3 to 5 times. There was no difference between the effect of optical isomers on the ChR of muscarinic type which mediate hyperpolarization in the neurones of the gastropod mollusc Planorbarius corneus. This suggest that some changes in ChR stereoselectivity may occur in the course of evolution.     

Effect of first-pass metabolism on enantioselective pharmacokinetics after oral administration of (+)-, (-)- and racemic homochlorcyclizine to rats

The enantioselective relationship between the pharmacokinetics and hepatic metabolism of homochlorcyclizine hydrochloride (HCZ) was investigated using rats. There were no significant differences in blood concentrations between the three forms after intravenous administration (5 mg/kg) of (+)-, (-)- and racemic HCZ. On the other hand, there were significant differences in the pharmacokinetics between (-)- and (+)-HCZ and between (-)- and racemic HCZ after oral administration (50 mg/kg) of these three forms. The Cmax and AUC0-infinity of (-)-HCZ were lower than those of (+)-isomer and racemate, and its CLo was clearly higher than the others. The (+)-isomer and racemate showed no significant differences in their pharmacokinetic parameters. At a lower dose (10 mg/kg), however, no enantiomeric differences were found in the pharmacokinetic parameters of (+)- and (-)-HCZ. Also examined was the cytochrome p-450-dependent-oxidative metabolism of (+)-, (-)- and racemic HCZ in vitro using rat liver 9000 x g supernatant fraction. The in vitro metabolism of (-)-HCZ was extremely fast, compared with those of the (+)-isomer and the racemate. The Vmax in vitro showed a good correlation with the CLo in vivo after oral administration (50 mg/kg) of all three forms of HCZ. In vitro study of enantiomeric inhibition of the metabolism showed that (+)-HCZ was a competitive inhibitor of (-)-HCZ metabolism, with a Ki of 6.96 microM. (-)-HCZ was also a competitive inhibitor of (+)-HCZ metabolism, with a Ki of 20.4 microM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and calcium channel modulating effects of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(thienyl)-5-pyridinecarboxylates

A group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(thienyl)-5-pyridinecarboxylates++ + 7a-f were prepared using a modified Hantzsch reaction that involved the condensation of a thienylcarboxaldehyde 4a-f with isopropyl 3-aminocrotonate 5 and nitroacetone 6. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compounds 7a-f exhibited weaker calcium channel antagonist activity (IC50 = 10(-5) to 10(-7) M range) than the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). The point of attachment of the C-4 thienyl ring system was a determinant of antagonist activity [3-thienyl (7b) > 2-thienyl (7a)]. A 5-substituent in the 2-thienyl moiety influenced antagonist activity where the potency order was 5-bromo-2-thienyl 7f > or = 5-methyl-2-thienyl 7c > 2-thienyl 7a. Although the 5-methyl-2-thienyl 7c and 3-methyl-2-thienyl 7d isomers are equipotent antagonists, the 5-bromo-2-thienyl compound 7f appears to be marginally more active than the 4-bromo-2-thienyl isomer 7e. The 2-thienyl compound 7a, unlike the 3-thienyl isomer 7b, exhibited an agonist effect on GPILSM in the absence of the muscarinic agonist carbachol. Effects of the 2-thienyl 7a and 3-thienyl 7b isomers on the magnitude of calcium current were determined in guinea pig ventricular myocytes with voltage clamp techniques. Results showed that 2-thienyl 7a inhibited calcium current (antagonist) when voltage steps were made from a potential of -40 mV. However, when voltage steps were made from -60 mV, 7a enhanced calcium current (agonist). The 3-thienyl isomer 7b had little, if any, effect on calcium current.     

High-performance liquid chromatographic determination of erdosteine and its optical active metabolite utilizing a fluorescent chiral tagging reagent, R-(-)-4-(N,N-dimethylamiosulfonyl)-7-(3-aminopyrrolidin-1-yl)-2 ,1,3-benzoxadiazole

Chiral separation of racemic M1 metabolized from erdosteine was investigated by reversed-phase chromatography. The sensitive determination of M1 and erdosteine with UV detection was difficult because of their low absorptivity in the effective wavelength region. To improve the sensitivity and separatability, one thiol and two carboxyl groups in the M1 structure were labelled with DBD-F and R-(-)-DBD-APy, respectively. Non-fluorescent DBD-F quantitatively reacted with thiol in M1 at room temperature for 30 min in borate buffer (pH 9.3) to produce the fluorescent derivative. On the other hand, the labelling of two carboxyls was carried out with a chiral fluorescent reagent, R-(-)-DBD-APy, in acetonitrile containing DPPA. The derivatives corresponding to a pair of the enantiomers were completely separated with water-acetonitrile containing 0.1% TFA as the mobile phase by an ODS column. Erdosteine with a carboxyl group was also labelled with R-(-)-DBD-APy and separated together with M1 derivatives. The detection limits (S/N=3) of erdosteine and M1 were 0.37 and 0.22 pmol, respectively. The proposed derivatization and separation methods were applied to simultaneous determination of racemic M1 and erdosteine in rat plasma after administration of erdosteine. The amounts of both enantiomers of M1 were essentially the same in oral and intravenous administrations. In contrast, total amounts (reduced-form and oxidized-form) of S-(-)-M1 in rat plasma were higher than those of R(+)-M1 in both administrations.     

Light is associated with a 34 kDa ribonucleoprotein in spinach chloroplasts

Ketamine exerts antinociceptive effects in many pain tests. We investigated the antinociceptive effect of intrathecally administered racemic ketamine and its S(+)- and R(-)-enantiomer on carrageenan-induced thermal hyperalgesia with a paw withdrawal test and acute pain (hot plate and tailflick) tests. Rats were prepared with a chronic lumbar intrathecal catheter to receive either saline or ketamine enantiomers in cumulative doses. None of the ketamines (10, 50, or 100 microg) had any effect on the withdrawal latency of the contralateral, noninjected paw. In the injected paw, intrathecal saline did not alter carrageenan-induced thermal hyperalgesia, whereas intrathecally applied S(+)-, R(-)-, and racemic ketamine decreased thermal hyperalgesia. However, compared with saline, racemic ketamine had a higher efficacy than S(+)-ketamine, whereas R(-)-ketamine did not achieve statistical significance. Neither S(+)- nor R(-)-ketamine had a significant effect in the tailflick test (10, 100, or 500 microg). In the hot plate test, only the largest dose of ketamine (500 microg) caused a nonstereospecific, significant increase in hot plate latency; this dose caused supraspinal effects as well. The results demonstrate that the behavioral hyperalgesia associated with carrageenan-induced hindpaw inflammation in rats is attenuated by the intrathecal administration of racemic and S(+)-ketamine, but not R(-)-ketamine, which only displayed an insignificant trend toward a dose-response relationship. This finding warrants further studies to investigate a possible clinical advantage of preservative-free S(+)-ketamine over the currently used preservative containing racemic mixture. IMPLICATIONS: In rats, intrathecal S(+)-ketamine was effective for treating inflammatory pain. Although racemic ketamine has a greater efficacy, S(+)-ketamine is available as a preservative-free drug and might be of clinical interest for future neuraxial administration in different pain states.     

Excitatory amino acid receptor antagonists: resolution, absolute stereochemistry, and pharmacology of (S)- and (R)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA)

We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation using N-BOC protected ATAA and (R)- and (S)-phenylethylamine. Enantiomeric purities (ee > 98%) of (R)- and (S)-ATAA were determined using the Crownpak CR(-) and CR(+) columns, respectively. The absolute configuration of (R)-ATAA was established by an X-ray crystallographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation (Ki > 1,000 microM).     

Intra-individual comparison of 3(R)-BMIPP and 3(S)-BMIPP isomers in humans

The racemic 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) is currently used at several centers for myocardial metabolic imaging with SPECT. Recently, the 3(R)-BMIPP isomer showed a 20%-25% higher myocardial uptake and lower liver uptake than 3(S)-BMIPP in fasted rats. The aim of this study was to determine if these differences in myocardial and liver uptake also occur in humans. METHODS: Iodine-123-labeled 3(R)-BMIPP and 3(S)-BMIPP isomers were injected at rest, on two separate days, in six patients with stable coronary artery disease. Dual-head, whole-body scintigraphy was performed 20 min and 3 hr after injection. SPECT cardiac imaging was performed 60 min after injection. RESULTS: Myocardial activity averaged (% injected dose +/- s.d.) 3.15 +/- 0.49 versus 3.01 +/- 0.44 at 20 min (p = ns) and 2.64 +/- 0.38 versus 2.55 +/- 0.41 at 3 hr postinjection (p = ns) for the 3(R)-BMIPP and 3(S)-BMIPP isomers, respectively. Liver activity averaged 9.50 +/- 1.18 versus 9.44 +/- 0.66 at 20 min and 5.33 +/- 0.64 versus 5.43 +/- 0.66 at 3 hr, respectively (p = ns). SPECT showed no difference in the distribution of the two isomers between normal and infarcted myocardium. CONCLUSION: There is no significant difference in myocardial and liver distribution of the 3(R)-BMIPP and 3(S)-BMIPP isomers in humans.     

Synthesis of (R,S)-10-methyloctadecanoic acid (tuberculostearic acid) and key chiral 2-methyl branched intermediates

Tuberculostearic acid, (R)-10-methyloctadecanoic acid, is a characteristic component of pathogenic mycobacteria and related organisms. Sensitive detection of this acid in infected material allows rapid detection of mycobacterial disease. A novel, convergent synthesis of tuberculostearic acid and key chiral intermediates is described in this communication, to provide a reference compound. Racemic and (R)- and (S)-1-iodo-2-methyldecanes were synthesised from 1-octanal and 1-carboethoxyethylidenetriphenylphosphorane as initial starting materials. 1-Hydroxyoct-7-yne was made from 1,6-hexanediol by two alternative methods and coupled with the above racemic iodide. Hydrogenation and oxidation of the resulting (R,S)-10-methyloctadec-7-yn-1-ol gave racemic tuberculostearic acid.     

The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg/kg of racemic, S(-), and R(+) phenprocoumon. S(-) phenprocoumon was 1.6 to 2.6 times as a potent as R(+) phenprocoumon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S(-) phenprocoumon was 1.5 to 2.5 times as potent as R(+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct difference in the rate of elimination between the enantiomers. The apparent volume of distribution and the plasma clearance for S(-) phenprocoumon were less than those for R(+) phenprocoumon. When the binding of the enantiomers to human serum albumin was compared, S(-) phenprocoumon was more highly bound than R(+) phenprocoumon. The protein binding of racemic phenprocoumon was between that of the enantiomers. The results show that S(-) phenprocoumon is more potent anticoagulant than R(+) phenprocoumon and that the pharmacokinetic differences between the enantiomers are due mainly to differences in their distribution.     

Metabolic fate of S-(-)-pulegone in rat

1. S-(-)-pulegone was administered orally to rat (250 mg/kg) and the nature of the urinary metabolites was investigated. Eleven metabolites, namely S-(-)-menthofuran, piperitone, piperitenone, p-cresol, 5-hydroxypulegone, 4-methylcyclohexenone, 3-methylcyclohexanone, isopulegone, pulegol, 7-hydroxypiperitone and benzoic acid, have been isolated from rat urine. It is assumed that menthofuran, isopulegone and 4-methylcyclohexenone retain the stereochemistry of the parent compound, whereas in other metabolites the stereochemistry at the asymmetric centres is not known. 2. The relative amounts of various major metabolites present in the total urine extracts from the R-(+) and S-(-)-pulegone-treated rat were established by glc analyses. Urine samples of rats treated with R-(+)-pulegone contained higher levels of p-cresol and piperitenone than in similar experiment carried out with S-(-)-pulegone, whereas the levels of unmetabolized pulegone, piperitone and benzoic acid were considerably higher in the urine of rat treated with S-(-)-pulegone than in a corresponding experiment with R-(+)-pulegone. 3. Phenobarbital-induced rat liver microsomes converted S-(-)-pulegone to S-(-)-menthofuran (VII) and piperitenone (III) in the presence of NADPH and O2. The levels of VII and III were significantly higher in similar experiments carried out with R-(+)-pulegone. 4. Based on these studies, metabolic pathways for the biotransformation of S-(-)-pulegone in rat have been proposed and possible reasons for the observed difference in the toxicity mediated by these two enantiomers are discussed.     

Synthesis and thromboxane A2 antagonistic activity of [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives

In order to find new antiasthmatic and antithrombotic agents, various [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives were synthesized. Evaluation of these compounds for thromboxane A2 (TXA2) antagonistic activities indicated that 4-[4-[(4-chlorobenzenesulfonamido)phenylmethyl]phenyl]butyric acid (6h) ,4-[4-[1-(4-chlorobenzenesulfonamido)-2-phenylethyl]phenyl]butyric acid (6y) and many other compounds have potent inhibitory effects on U-46619-induced guinea-pig platelet aggregation. No significant difference in the inhibitory effect between (+)-6h and its antipode could be detected, although (+)-6h and its antipode could be detected, although (+)-6y was about 10 times more potent than (-)6y. The pKb values of 6h and 6y were estimated to be 8.9 and 10, respectively on U-46619-induced contraction of guinea-pig trachea as a pharmacological measure of TXA2 antagonistic activity. These compounds also showed potent inhibitory effects on U-46619-induced bronchoconstriction in guinea-pig after oral administration in vivo. They were also evaluated for other related pharmacological effects involving the arachidonic acid cascade. It was found that these compounds possess TXA2 synthase inhibitory activity together with TXA2 antagonistic activity, and 6h also possesses weak leukotriene D4 (LTD4) antagonistic activity. Structure-activity relationships for TXA2 antagonistic activity of these derivatives are discussed.