Comparison of interactions of R-(+)- and S-(-)-isomers of beta-adrenergic partial agonists, befunolol and carteolol, with high affinity site of beta-adrenoceptors in isolated rabbit ciliary body and guinea-pig taenia caeci.

The stereoselectivities of beta-adrenergic partial agonists for the high affinity binding site of beta-adrenoceptors in the rabbit ciliary body and the guinea-pig taenia caeci were studied. The pA2 values of the S-(-)-isomers of befunolol and carteolol against S-(-)-isoprenaline, which were calculated from the shift of each concentration - response curve in increasing cyclic AMP levels, were significantly larger than those of the R-(+)-isomers in the guinea-pig taenia caeci, while the pA2 values of the S-(-)-isomers were not significantly larger than those of the R-(+)-isomers in the rabbit ciliary body. The pK1 values determined from the binding experiments were in good agreement with the pA2 values from the increases in cyclic AMP levels. These results suggest that the high affinity binding site of beta-adrenoceptors in the guinea-pig taenia caeci may be able to discriminate stereoselectively between the R-(+)- and S-(-)-isomers, while in the rabbit ciliary body there is no stereo-selectivity between the two enantiomers.     

Behavioral and radioreceptor analysis of viloxazine stereoisomers

The differences in the pharmacological effects of R(+)- and S(-)-isomers of the atypical antidepressant viloxazin were discovered in two behavioral models. The S(-)-isomer appeared 5 times as active as the R(+)-isomer under acute administration. In chronic administration, (15 days), the R(+)-isomer appeared ineffective. Comparison of the affinity of the racemate, R(+) and S(-)-isomers for alpha 1-, alpha 2- and beta-adrenoreceptors, as well as for serotonin, C1, benzodiazepine, imipramine and dopamine receptors did not demonstrate any stereospecificity of viloxazin isomers. It is assumed that some other receptors (histamine, acetylcholine) present the targets for the pharmacological action of viloxazin or the latter one has, like zimelidin , specific binding sites of its own.     

Biosynthesis of monoterpenes. Enantioselectivity in the enzymatic cyclization of (+)- and (-)-linalyl pyrophosphate to (+)- and (-)-pinene and (+)- and (-)-camphene

Cyclase I from Salvia officinalis leaf catalyzes the conversion of geranyl pyrophosphate to the stereo-chemically related bicyclic monoterpenes (+)-alpha-pinene and (+)-camphene and to lesser quantities of monocyclic and acyclic olefins, whereas cyclase II from this plant tissue converts the same acyclic precursor to (-)-alpha-pinene, (-)-beta-pinene and (-)-camphene as well as to lesser amounts of monocyclics and acyclics. These antipodal cyclizations are considered to proceed by the initial isomerization of the substrate to the respective bound tertiary allylic intermediates (-)-(3R)- and (+)-(3S)-linalyl pyrophosphate. [(3R)-8,9-14C,(3RS)-1E-3H]Linalyl pyrophosphate (3H:14C = 5.14) was tested as a substrate with both cyclases to determine the configuration of the cyclizing intermediate. This substrate with cyclase I yielded alpha-pinene and camphene with 3H:14C ratios of 3.1 and 4.2, respectively, indicating preferential, but not exclusive, utilization of the (3R)-enantiomer. With cyclase II, the doubly labeled substrate gave bicyclic olefins with 3H:14C ratios of from 13 to 20, indicating preferential, but not exclusive, utilization of the (3S)-enantiomer in this case. (3R)- and (3S)-[1Z-3H]linalyl pyrophosphate were separately compared to the achiral precursors [1-3H]geranyl pyrophosphate and [1-3H]neryl pyrophosphate (cis-isomer) as substrates for the cyclizations. With cyclase I, geranyl, neryl, and (3R)-linalyl pyrophosphate gave rise exclusively to (+)-alpha-pinene and (+)-camphene, whereas (3S)-linayl pyrophosphate produced, at relatively low rates, the (-)-isomers. With cyclase II, geranyl, neryl, and (3S)-linalyl pyrophosphate yielded exclusively the (-)-isomer series, whereas (3R)-linalyl pyrophosphate afforded the (+)-isomers at low rates. These results are entirely consistent with the predicted stereochemistries and additionally revealed the unusual ability of these enzymes to catalyze antipodal cyclizations when presented with the unnatural linalyl enantiomer.     

Formation of glycine conjugate and (-)-(R)-enantiomer from (+)-(S)-2-phenylpropionic acid suggesting the formation of the CoA thioester intermediate of (+)-(S)-enantiomer in dogs.

It has been proposed that the chiral inversion of the 2-arylpropionic acids is due to the stereospecific formation of the (-)-R-profenyl-CoA thioesters which are putative intermediates in the inversion. Accordingly, amino acid conjugation, for which the CoA thioesters are obligate intermediates, should be restricted to those optical forms which give rise to the (-)-R-profenyl-CoA, i.e., the racemates and the (-)-(R)-isomers. We have examined this problem in dogs with respect to 2-phenylpropionic acid(2-PPA). Regardless of the optical configuration of 2-phenylpropionic acid administered, the glycine conjugate was the major urinary metabolite and this was shown to be exclusively the (+)-(S)-enantiomer by chiral HPLC. Both (-)-(R)- and (+)-(S)-2-phenylpropionic acid were present in plasma after the administration of either antipode, and further evidence of the chiral inversion of both enantiomers was provided by the presence of some 25% of the opposite enantiomer in the free 2-phenylpropionic acid and its glucuronide excreted in urine after administration of (-)-(R)- and (+)-(S)-2-phenylpropionic acid. The (+)-(S)-enantiomer underwent chiral inversion to the (-)-(R)-antipode when incubated with dog hepatocytes. These data suggests that both enantiomers of 2-phenylpropionic acid are substrates for canine hepatic acyl CoA ligase(s) and thus undergo chiral inversion, but that the CoA thioester of only (+)-(S)-2-phenylpropionic acid is a substrate for the glycine N-acyl transferase. These studies are presently being extended to the structure and species specificity of the reverse inversion and amino acid conjugation of profen NSAIDs.     

Interactions of some partial agonists with high and low affinity binding sites in beta-adrenoceptors

Interactions of derivatives of befunolol (BFE-37, BFE-55, and BFE-61), carteolol, and pindolol with beta-adrenoceptors were tested in guinea pig isolated taenia caecum. All the drugs used acted as partial agonists on the beta-adrenoceptors when compared with isoprenaline, a full agonist. The pA2 values of BFE-61, carteolol, and pindolol were significantly larger than their pD2 values, while there was no significant difference between the pA2 and pD2 values for BFE-37 and BFE-55. The specific binding of [3H]befunolol to microsomal fractions from the guinea pig taenia caecum distinguished two binding sites, high affinity and low affinity sites. Both sites are considered to be bound by 50 nM of [3H]befunolol. Specific 3H binding was displaced by BFE-61, carteolol, and pindolol in a biphasic manner but in a monophasic manner by BFE-37 and BFE-55. Furthermore, [3H]befunolol binding was only partially displaced by BFE-55 but completely displaced by the other drugs used. These results, together with our previous findings, suggest that BFE-61, carteolol, and pindolol discriminate between the two affinity binding sites in the beta-adrenoceptors, which are not discriminated between by BFE-37, and further that BFE-55 may bind with only the high affinity site.     

Comparative Stereostructure-Activity Studies on GABAA and GABAB Receptor Sites and GABA Uptake Using Rat Brain Membrane Preparations

The affinities of a number of analogues of gamma-aminobutyric acid (GABA) for GABAA and GABAB receptor sites and GABA uptake were studied using rat brain membrane preparations. Studies on the (S)-(+)- and (R)-(-)-isomers of baclofen, 3-hydroxy-4-aminobutyric acid (3-OH-GABA), and 4,5-dihydromuscimol (DHM) revealed different stereoselectivities of these synaptic mechanisms in vitro. Although (S)-3-OH-GABA and, in particular, (S)-DHM were more potent than the corresponding (R)-isomers as inhibitors of GABAA binding, the opposite stereoselectivity was demonstrated for the GABAB binding sites. Thus, (R)-3-OH-GABA and (R)-baclofen were more potent than the (S)-isomers as inhibitors of GABAB binding, (R)-baclofen being some five times more potent than (R)-3-OH-GABA. These two (R)-isomers actually have opposite orientation of the substituents on the GABA backbones, suggesting that the lipophilic substituent of (R)-baclofen interacts with a structural element of the GABAB receptor site different from that that binds the very polar hydroxy group of (R)-3-OH-GABA. The O-methylated analogue of 3-OH-GABA, 3-methoxy-4-aminobutyric acid (3-OCH3-GABA), did not interact significantly with GABAB sites. The homologues of GABA, trans-4-aminocrotonic acid (trans-ACA), muscimol, and 3-OH-GABA, that is, 5-aminovaleric acid (DAVA), trans-5-aminopent-2-enoic acid, homomuscimol, and 3-hydroxy-5-aminovaleric acid (3-OH-DAVA), respectively, were generally much weaker than the parent compounds, whereas 2-hydroxy-5-aminovaleric acid (2-OH-DAVA) showed a significantly higher affinity for GABAB sites than the corresponding GABA analogue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development and validation of a chiral liquid chromatographic method, based on Chiralpak to quantify enantiomers of (+/-)-DRF 2725 in rat plasma: lack of inversion of ragaglitazar (S(-)-DRF 2725) to its antipode in plasma

A selective, accurate and reproducible high-performance liquid chromatographic (HPLC) method for the separation of individual enantiomers of DRF 2725 [R(+)-DRF 2725 and S(-)-DRF 2725 or ragaglitazar] was obtained on a chiral HPLC column (Chiralpak). During method optimization, the separation of enantiomers of DRF 2725 was investigated to determine whether mobile phase composition, flow-rate and column temperature could be varied to yield the base line separation of the enantiomers. Following liquid-liquid extraction, separation of enantiomers of DRF 2725 and internal standard (I.S., desmethyl diazepam) was achieved using an amylose based chiral column (Chiralpak AD) with the mobile phase, n-hexane-propanol-ethanol-trifluoro acetic acid (TFA) in the ratio of 89.5:4:6:0.5 (v/v). Baseline separation of DRF 2725 enantiomers and I.S., free from endogenous interferences, was achieved in less than 25 min. The eluate was monitored using an UV detector set at 240 nm. Ratio of peak area of each enantiomer to I.S. was used for quantification of plasma samples. Nominal retention times of R(+)-DRF 2725, S(-)-DRF 2725 and I.S. were 15.8, 17.7 and 22.4 min, respectively. The standard curves for DRF 2725 enantiomers were linear (R(2) > 0.999) in the concentration range 0.3-50 microg/ml for each enantiomer. Absolute recovery, when compared to neat standards, was 70-85% for DRF 2725 enantiomers and 96% for I.S. from rat plasma. The lower limit of quantification (LLOQ) for each enantiomers of DRF 2725 was 0.3 microg/ml. The inter-day precisions were in the range of 1.71-4.60% and 3.77-5.91% for R(+)-DRF 2725, S(-)-DRF 2725, respectively. The intra-day precisions were in the range of 1.06-11.5% and 0.58-12.7% for R(+)-DRF 2725, S(-)-DRF 2725, respectively. Accuracy in the measurement of quality control (QC) samples was in the range 83.4-113% and 83.3-113% for R(+)-DRF 2725, S(-)-DRF 2725, respectively. Both enantiomers and I.S. were stable in the battery of stability studies viz., bench-top (up to 6 h), auto-sampler (up to 12 h) and freeze/thaw cycles (n = 3). Stability of DRF 2725 enantiomers was established for 15 days at -20 degrees C. The application of the assay to a pharmacokinetic study of ragaglitazar [S(-)-DRF 2725] in rats is described. It was unequivocally demonstrated that ragaglitazar does not undergo chiral inversion to its antipode in vivo in rat plasma.     

Stereoselective synthesis of (22R)- and (22S)-castasterone/ponasterone A hybrid compounds and evaluation of their molting hormone activity

Two stereoisomers of a castasterone/ponasterone A hybrid compound, the (20R,22R) and (20R,22S)-isomers of 2alpha,3alpha,20,22-tetrahydroxy-5alpha-cholestan-6-one, were synthesized stereoselectively and their binding activity to the ecdysteroid receptor was determined. From the concentration-response curve for the inhibition of the incorporation of tritiated ponasterone A into ecdysteroid receptor containing insect cells, the concentration (IC50) required to inhibit 50% of the incorporation of radioactivity into cells was evaluated. The IC50 values of the (22R)- and (22S)-isomers were determined to be 0.30 and 38.9 microM against Kc cells, respectively, indicating that the (22R)-isomer is about 100 times more potent than the corresponding (22S)-isomer. IC50 values of these compounds against lepidopteran Sf-9 cells were determined to be 0.36 and 12.9 microM, respectively. The molting hormonal effect was examined in a Chilo suppressalis integument system and the 50% effective concentration for the stimulation of N-acetylglucosamine incorporation into the cultured integument was determined to be 2.7 microM for the (22R)-isomer, while the (22S)-isomer was inactive. On the other hand, both isomers did not show brassinolide-like activity in the rice lamina inclination assay.     

A dopamine D3 receptor agonist, 7-OH-DPAT,causes vomiting in the dog

R(+)7-hydroxy-N,N-di-n-propyl-2-aminotetralin (R(+)-7-OH-DPAT), a selective dopamine D₃ receptor agonist, (0.03–0.3 mg/Kg, S.c.) dose-relatedly caused emesis, whereas S (−)-7-OH-DPAT at even 1 mg/kg did not induce emesis in dogs. Apomorphine (0.03-0.3 mg/kg, s.c.) or quinpirole (0.03–0.1 mg/Kg, S.c.) also caused emesis in a dose-dependent manner. The potency of R(+)-7-OH-DPAT in inducing emesis was the same as that of apomorpine and quipirole. On the other hand, SKF-38393 (1 and 3 mg/Kg, S.c.), a selective d₁ receptor agonist, failed to induce emesis in dogs. The emesis induced by R(+)-7-OH-DPAT (0.3 mg/Kg, S.c.) was inhibited by S(−)-eticlopride (0.01–0.1 mg/Kg, S.c.), a potent D₂ and D₃ receptor antagonist but not by SCH-23390 (1 mg/Kg, S.c.), a selective d₁ receptor antagonist or clozapine (1 mg/Kg, S.c.), a D₄ receptor antagonist. These results indicate that dopamine D₃ receptors play an important role in the genesis of emesis in dogs.     

Enantioselective detoxication of optical isomers of glycidyl ethers

The detoxication of the enantiomers of glycidyl 4-nitrophenyl ether (GNPE), (?)-(R)- and (+)-(S)-GNPE, and glycidyl 1-naphthyl ether (GNE), (?)-(R)- and (+)-(S)-GNE, by rat liver glutathione transferase and epoxide hydrolase was studied. Enantioselectivity was observed with both enzymes favoring the (R)-isomers as determined by the formation of conjugate, diol, and remaining substrate measured by HPLC. Enantiomers of GNE were detoxified by cytosolic epoxide hydrolase but those of GNPE were not. Substantial nonenzymatically formed conjugates of enantiomers of GNPE were detected showing (S)-GNPE the more reactive of the pair. © 1993 Wiley-Liss, Inc.     

Systematic strategy for the synthesis of cyanobacterin and its stereoisomers. 2. Asymmetric total synthesis of the 2- and 3-epimers of dechloro-cyanobacterin

Stereocontrolled total syntheses of the (2S,3R)- and (2R,3S)-isomers of the non-chlorinated analog of cyanobacterin, a potent photosynthesis inhibitor, were achieved. Since both the (2R,3R)- and (2S,3S)-isomers of this compound had been previously synthesized from the same starting material, a systematic strategy for the synthesis of all stereoisomers could be established.     

Synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)- 6-hydroxy-3,5-dimethyl-2-octanone,the pheromone components of the bostrychid beetle,Dinoderus bifoveolatus

(4R,6S,7R)-7-Hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone, the pheromone components of the bostrychid beetle, Dinoderus bifoveolatus, as well as their (4R,6S,7S)- and (3R,5S,6S)-isomers were synthesized from (2R,4S,5R)- and (2R,4S,5S)-2,4-dimethyl-5-heptanolide, respectively.     

Differential effects of intravenous R,S-(+/-)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(-)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core

R,S(+/-)-3,4-methylenedioxymethamphetamine (R,S(+/-)-MDMA, 'Ecstasy') is known to stimulate dopamine (DA) transmission in the nucleus accumbens (NAc). In order to investigate the post-synaptic correlates of pre-synaptic changes in DA transmission and their relationship with MDMA enantiomers, we studied the effects of R,S(+/-)-MDMA, S(+)-MDMA, and R(-)-MDMA on extracellular DA and phosphorylated extracellular signal regulated kinase (pERK) in the NAc shell and core. Male Sprague-Dawley rats, implanted with a catheter in the femoral vein and vertical concentric dialysis probes in the NAc shell and core, were administered i.v. saline, R,S(+/-)-MDMA, S(+)-MDMA, or R(-)-MDMA. Extracellular DA was monitored by in vivo microdialysis with HPLC. Intravenous R,S(+/-)-MDMA (0.64, 1, and 2 mg/kg) increased dialysate DA, preferentially in the shell, in a dose-related manner. S(+)-MDMA exerted similar effects but at lower doses than R,S(+/-)-MDMA, while R(-)-MDMA (1 and 2 mg/kg) failed to affect dialysate DA. R,S(+/-)- and S(+)-MDMA but not R(-)-MDMA increased ERK phosphorylation (expressed as density/neuron and number of pERK-positive neurons/area) in both subdivisions of the NAc. The administration of the D1 receptor antagonist, SCH 39166, prevented the increase in pERK elicited by R,S(+/-)-MDMA and S(+)-MDMA, while the D2/3 receptor antagonist, raclopride, increased pERK in the NAc core per se but failed to affect the R,S(+/-)-MDMA-elicited stimulation of pERK. The present results provide evidence that the DA stimulant effects of racemic MDMA are accounted for by the S(+)-enantiomer and that pERK may represent a post-synaptic correlate of the stimulant effect of R,S(+/-)-MDMA on D1-dependent DA transmission.     

Regulation of lettuce hypocotyl elongation by gibberellic acid. Interaction of gibberellic acid and gibberellin synergists - dihydroconiferyl alcohol, pestalotin and a triazinone compound

The effect of three gibberellin synergists on lettuce hypocotylelongation was studied. Dihydroconiferyl alcohol isolated fromlettuce plants and (–)-(6S, 1'S)-pestalotin isolated fromPestalotia cryptomeriaecola enhanced the promoting effect ofgibberellic acid on hypocotyl elongation of lettuce seedlingswith and without the cotyledons. On the other hand, TA, a triazinonecompound, did not enhance the gibberellin effect. The actionof (–)-(6S, 1'S)-pestalotin was strongly inhibited bycompetitive inhibitors of dihydroconiferyl alcohol such as caffeic,ferulic and trans-cinnamic acids. Of the two stereoisomers ofpestalotin, (+)-(6R, 1'R)-pestalotin enhanced the gibberellineffect but (+)-(6R, 1'S)-epipestalotin did not. (+)-(6R, 1'S)-Epipestalotinstrongly inhibited the action of (–)-(6S, 1'S)-pestalotinand dihydroconiferyl alcohol. TA did not affect the action ofdihydroconiferyl alcohol. Stress-relaxation analysis of the mechanical properties of thelettuce hypocotyl cell wall demonstrated that gibberellic acidcaused cell wall loosening and dihydroconiferyl alcohol andpestalotin did not influence this gibberellin effect. The action mechanism of gibberellin synergists is discussedbased on these results. (Received December 22, 1978; )     

Biosynthesis of monoterpenes. Stereochemistry of the enzymatic cyclizations of geranyl pyrophosphate to (+)-alpha-pinene and (-)-beta-pinene

The conversion of geranyl pyrophosphate to (+)-alpha-pinene and to (-)-beta-pinene is considered to proceed by the initial isomerization of the substrate to (-)-(3R)- and to (+)-(3S)-linalyl pyrophosphate, respectively, and the subsequent cyclization of the anti, endo-conformer of these bound intermediates by mirror-image sequences which should result in the net retention of configuration at C1 of the geranyl precursor. Incubation of (1R)-[2-14C,1-3H]- and (1S)-[2-14C,1-3H]geranyl pyrophosphate with (+)-pinene cyclase and with (-)-pinene cyclase from common sage (Salvia officinalis) gave labeled (+)-alpha- and (-)-beta-pinene of unchanged 3H/14C ratio in all cases, and the (+)- and (-)-olefins were stereoselectively converted to (+)- and (-)-borneol, respectively, which were oxidized to the corresponding (+)- and (-)-isomers of camphor, again without change in isotope ratio. The location of the tritium was determined in each case by stereoselective, base-catalyzed exchange of the exo-alpha-hydrogens of these derived ketones. The results indicated that the configuration at C1 of the substrate was retained in the enzymatic transformations to the (+)- and (-)-pinenes, which is entirely consistent with the syn-isomerization of geranyl pyrophosphate to linalyl pyrophosphate, transoid to cisoid rotation, and anti, endo-cyclization of the latter. The absolute stereochemical elements of the antipodal reaction sequences were confirmed by the selective enzymatic conversions of (3R)- and (3S)-1Z-[1-3H]linalyl pyrophosphate to (+)-alpha-pinene and (-)-beta-pinene, respectively, and by the location of the tritium in the derived camphors as before. The summation of the results fully defines the overall stereochemistry of the coupled isomerization and cyclization of geranyl pyrophosphate to the antipodal pinenes.     

Biomimetic conversion of (3S)-(-)-neodictyoprolenol to optically pure (1S,2R)-(-)-dictyopterene B,marine algal sex pheromone

Both enantiomers of (3S)-(-)- and (3R)-(+)-Neodictyoprolenol [(3S,5Z,8Z)-(-)-1,5,8-undecatrien-3-ol] were successfully converted to the algal sex pheromone, (1S,2R)-(-)-dictyopterene B and (1R,2S)-(+)-dictyopterene B in high enantiomeric purities (e. e. > 99%), respectively, by the biomimetic reaction involving phosphorylation and elimination under a mild condition.     

AMPA receptor agonists: Resolution,configurational assignment,and pharmacology of (+)-(S)- and (-)-(R)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-isoxazol-4-yl]-propionic acid (2-Py-AMPA)

We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonist and (R)-APPA a weak competitive AMPA receptor antagonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee ≥ 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [³H]AMPA binding (IC⁵⁰ = 0.19 ± 0.06 μM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC₅₀ = 4.5 ± 0.3 μM) comparable with AMPA (IC₅₀ = 0.040 ± 0.01 μM; EC₅₀ = 3.5 ± 0.2 μM), but much more potent than (+)-(S)-APPA (IC₅₀ = 5.5 ± 2.2 μM; EC₅₀ = 230 ± 12 μM). Like (-)-(R)-APPA (IC₅₀ > 100 μM), (-)-(R)-2-Py-AMPA (IC₅₀ > 100 μM) did not significantly affect [³H]AMPA binding, and both compounds were week AMPA receptor antagonists (K_i = 270 ± 50 and 290 ± 20 μM, respectively). Chirality 9:274–280, 1997. © 1997 Wiley-Liss, Inc.     

Biomimetic synthesis of acid-sensitive (-)- and (+)-caparrapi oxides, (-)- and (+)-8-epicaparrapi oxides, and (+)-dysifragin induced by artificial cyclases

Asymmetric total syntheses of acid-sensitive (-)- and (+)-caparrapi oxides (1) and (+)-8-epicaparrapi oxide (2) from farnesol (10) are achieved using Sharpless-Katsuki epoxidation and Lewis acid-assisted chiral Br?nsted acid (chiral LBA)-induced polyene cyclization as key steps. The relative configuration of (+)-dysifragin (4) is determined by a single-crystal X-ray diffraction and its total synthesis is accomplished by the diastereoselective epoxidation of (+)-1. Furthermore, (-)-1 can be directly synthesized from (S)-nerolidol (3) and (R)-LBA with 88% ds by reagent control, which overcame substrate control, while (-)-2 is obtained from (R)-3 and (R)-LBA with >99% ds by the double asymmetric induction.     

Toxicity of (22R,23R)-22,23-dihydroxystigmastane derivatives to cultured cancer cells

Toxicity of eight 22,23-dihydroxystigmastane derivatives (four pairs of (22R,23R)- and (22S,23S)-isomers differing in steroid backbone structure) to human breast carcinoma MCF-7 cells was compared. For every pair of structurally related compounds, (22R,23R) isomer was found to be significantly more toxic than (22S,23S) isomer. Computational analysis showed that side chain of (22R,23R)-22,23-dihydroxystigmastane derivatives is rigid, whereas that of (22S,23S)-isomers is rather flexible. Structure of steroid backbone significantly affects cytotoxicity of (22R,23R)-22,23-dihydroxystigmastane derivatives to human breast carcinoma MCF-7 cells, human ovary carcinoma CaOv cells, and human prostate carcinoma LnCaP cells. (22R,23R)-3β,22,23-trihydroxystigmast-5-ene and (22R,23R)-3β,22,23-trihydroxystigmast-5-en-7-one, both comprising equatorial 3β-hydroxyl group, exhibited the highest cytotoxicity, while the most polar 28-homobrassinolide and 28-homocastasterone, both comprising 2α,3α-dihydroxy groups, exhibited the lowest toxicity. Binding of (22R,23R)-22,23-dihydroxystigmastane derivatives to plasmatic membrane was suggested to be important for cytotoxicity.     

Influence of the chirality of (R)-(-)- and (S)-(+)-carvone in the central nervous system: a comparative study

Many terpenes are used therapeutically, and as flavor and fragrance materials. (R)-(-)-Carvone, the main constituent of spearmint oil, and (S)-(+)-carvone, found as major component of caraway and dill seed oils, have several applications and are used in cosmetic, food, and pharmaceutical preparations. In this study, the effect of enantiomers of carvone on the central nervous system (CNS) was evaluated in mice. The LD50 value was 484.2 mg/kg (358.9-653.2) for (S)-(+)-carvone, and 426.6 (389.0-478.6) mg/kg for (R)-(-)-carvone. Both enantiomers caused depressant effects, such as decrease in the response to the touch and ambulation, increase in sedation, palpebral ptosis, and antinociceptive effects. (S)-(+)- and (R)-(-)-carvone caused a significant decrease in ambulation. (R)-(-)-Carvone appeared to be more effective than its corresponding enantiomer at 0.5 and 2.0 h after administration. However, (S)-(+)-carvone was slightly more potent at 1 h. In potentiating pentobarbital sleeping time, (R)-(-)-carvone was more effective than (S)-(+)-carvone at 100 mg/kg, but was less potent at 200 mg/kg compared to the (+)-enantiomer, indicating a sedative action. (S)-(+)-Carvone at the dose of 200 mg/kg increased significantly the latency of convulsions induced by PTZ and PIC, but (R)-(-)-carvone was not effective against these convulsions. These results suggest that (S)-(+)-carvone and (R)-(-)-carvone have depressant effect in the CNS. (S)-(+)-Carvone appears to have anticonvulsant-like activity.