摘要:

AbstractThe activities of the enantiomers of BM‐5 were examined to measure muscarinic cholinergic selectivity in the central nervous system. Autoradiographic studies assessed the ability of each enantiomer to inhibit the binding of [3H]‐(R)‐quinuclidinyl benzilate ([3H]‐(R)‐QNB) to muscarinic receptors in the rat brain. (+)‐(R)‐BM‐5 inhibited [3H]‐(R)‐QNB binding to rat brain sections at concentrations below 1.0 μM, while 100‐fold higher concentrations of (—)‐(S)‐BM‐5 were required for comparable levels of inhibition. Analysis of the autoradiograms indicated that both stereoisomers had a similar distribution of high affinity binding sites. Each enantiomer displayed higher affinity for muscarinic receptors in the superior colliculi and lower affinity for receptors in the cerebral cortex and hippocampus. (+)‐(R)‐BM‐5 and oxotremorine inhibited adenylyl cyclase activity in the cerebral cortex with efficacies comparable to that for acetylcholine. (+)‐(R)‐BM‐5 was 26‐fold more potent than (—)‐(S)‐BM‐5 in inhibiting adenylyl cyclase. Oxotremorine‐M and carbamylcholine stimulated phosphoinositide turnover in the cerebral cortex. Oxotremorine had lower activity and (+)‐(R)‐BM‐5 was essentially inactive at comparable concentrations. The difference in activity of the two enantiomers indicates a remarkable stereochemical selectivity for muscarinic receptors. The stereoselectivity index is comparable for both the autoradiographic assays (48) and measures of adenylyl cyclase

ISSN:0899-0042    

DOI:10.1002/chir.530040802

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractFormation of metabolic intermediate (MI) complexes was studied with the enantiomers of amphetamine, 1‐phenyl‐2‐pentanamine,N‐hydroxyamphetamine, and 2‐nitroso‐1‐phenylpropane (theC‐nitroso analogue of amphetamine). Three different enzyme systems were used; liver microsomes from phenobarbital pretreated rats and two reconstituted systems containing the P450 2B1 and P450 2C11 forms of cytochrome P‐450. Enantioselective complex formation in microsomes was shown for the amines and the nitroso compound, but not for the hydroxylamine. The highly purified P450 2B1 system formed the MI complex with all substrates tested, and the enantioselectivity observed with the microsomal system was reproduced. In the P450 2C11 system the nitroso compounds were completely inactive, whereas the enantiomers ofN‐hydroxyamphetamine still produced the complex at a high rate. Changes in temperature were shown to affect (R)‐2‐nitroso‐1‐phenylpropane more than its enantiomer. Both enantiomers showed biphasic Arrhenius plots for MI complex formation in microsomes (breaks around 22°C), but the activation energies of the (R)‐isomer were about five times higher than those of the (S)‐isomer. A theory is presented which suggests different modes of interaction with the active site of P‐450 to account for the different behaviour of the various

ISSN:0899-0042    

DOI:10.1002/chir.530040803

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe stereoselectivity of the peroxisome proliferation potency of 2‐ethylhexanoic acid (2‐EHA), a metabolite of the plasticizer di‐(2‐ethylhexyl) adipate, was investigated in vitro. The enantiomers of 2‐EHA were prepared via the semipreparative HPLC resolution of their diastereoisomeric (+)‐(R)‐1‐phenylethylamine derivatives and the subsequent hydrolytic cleavage. Monolayers of hepatocytes were incubated 3 days with solutions of (—)‐(R), (+)‐(S), and (±)‐2‐EHA. The peroxisome proliferation potency was measured by means of determination of the peroxisomal palmitoyl coenzyme A oxidation. The theoretical induction component due to each enantiomer were calculated from the experimental data considering the enantiomeric purities of the acids. The (+)‐(S)‐enantiomer was found to be the most potent inducer, e.g., the eutomer, while the (—)‐(R) was the distomer. The eudismic ratio was about 1.6 and the racemic mixture exhibited an intermediary potency. These results, obtained in vitro in conditions avoiding confounding factors such as pharmacokinetics, suggest that the peroxisome proliferation induced by 2‐ethylhexanoic acid is a stereoselectiv

ISSN:0899-0042    

DOI:10.1002/chir.530040804

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe pharmacological activity of ketoprofen enantiomers was investigated in humans by an in vitro method. The antiplatelet effect of ketoprofen was assessed by measuring the inhibition of platelet thromboxane B2(TXB2) generation during the controlled clotting of whole blood obtained from each of four healthy volunteers. Ketoprofen was added separately to whole blood as a range of concentrations of (1) predominantly (S)‐ketoprofen, (2) racemic ketoprofen, and (3) predominantly (R)‐ketoprofen. (S)‐Ketoprofen was found to be solely active at inhibiting human platelet TXB2production; (R)‐ketoprofen was devoid of such activity and did not modify the potency of its optical antipode. A relationship between the percentage inhibition of TXB2generation and the unbound concentration of (S)‐ketoprofen in serum was modelled according to a sigmoidal Emaxequation. The mean (±SD) serum unbound concentration of (S)‐ketoprofen required to inhibit platelet TXB2generation by 50% (EC50) was 0.320 (±0.062) ng/ml. This value for ketoprofen is considerably lower than previously reported values for (S)‐ibuprofen and (S)‐naproxen. © 19

ISSN:0899-0042    

DOI:10.1002/chir.530040805

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractAn achiral/chiral high‐performance liquid chromatographic system for the analysis of total warfarin together with the (R)‐ and (S)‐enantiomers in clinical samples has been developed. The achiral analysis is achieved using a C8column, which is coupled to a chiral stationary phase, α1‐acid glycoprotein (AGP), thereby allowing for analysis of warfarin isomers without interfering serum peaks. A 0.015Mphosphate buffer mobile phase with 15% v/v propan‐2‐ol (pH 7.0) was used on the C8/AGP system. UV analysis at 308 nm was used for quantitation of total warfarin on the C8column and fluorescence (excitation 300 nm, emission 390 nm) detection was employed for isomer quantitation on the AGP. Retention time of total warfarin on the C8column was 5.95 min, while that of the (S)‐ and (R)‐warfarin on the AGP column was 10.38 and 12.69 min, respectively. Peak resolution of the warfarin isomers was 1.64. All serum samples were subjected to solid‐phase extraction. Data from two patients in a single dose study indicate that a two‐compartmental model could represent the warfarin concentration—time data with enterohepatic circulation. In some patients studied during steady state therapy, concentrations of (S)‐warfarin were greater than (R)‐warfarin indicating that the clearance of the former is slower in these patien

ISSN:0899-0042    

DOI:10.1002/chir.530040806

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractResolution of mandelic acid with (—)‐(1R,2S)‐ephedrine in water and ethanol produces intermediate diastereomeric salts with greatly disparate solubilities and melting points. Single crystal X‐ray analysis of the less (L) and more (M) soluble (—)‐ephedrinium mandelates (I, II) shows crystal structures which are isosteric, each crystallizing in the monoclinic system, space groupC2. Protonated ephedrines occupy the same relative positions in the L‐ and M‐salts, and mandelates are in the same general locations. Hydrogen bonds link alternating protonated ephedrine nitrogens and mandelate carboxylate oxygens in each salt forming columns of ions. The helical H‐bonded chain winds down the crystallographic 2‐fold screw axis. Additional H‐bonds form between 2‐fold related mandelates in the L‐salt. Mixed crystals, containing both mandelate isomers, (2R)‐ and (2S)‐mandelates, are obtained from the resolving system partly depleted of the L‐salt. A specimen with nearly equal amounts of the mandelates (III) is also isosteric with the commensurate structures.I(294K), L‐salt:a= 18.160(7),b= 6.538(2),c= 13.898(4) Å, β = 92.02(3)°,V= 1649.1(9) Å3;IIa(294K), M‐salt:a= 17.978(11),b= 7.164(4),c= 13.574(6)Å, β = 96.41(4)°,V= 1737.3(16) Å3;IIb(223K), M‐salt:a= 17.805(8),b= 7.115(2),c= 13.50(5) Å, β = 96.89(3)°,V= 1697.9(15) Å3;III(294K), mixed‐salt:a= 18.184(22),b= 6.792(7),c= 13.808(19) Å, β

ISSN:0899-0042    

DOI:10.1002/chir.530040807

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

ISSN:0899-0042    

DOI:10.1002/chir.530040808

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractA reversed‐phase coupled column separation (CCS) system for the analysis of two diastereomeric glucuronides of almokalant, a new class III antiarrhythmic drug, in human urine is described. After direct injection of urine samples (50 μl) the glucuronides were isolated by complex formation on a terbium(III) loaded strong cation exchanger at alkaline pH. The solutes were eluted from the precolumn by an acidic mobile phase, enriched and separated on Hypercarb (porous graphitic carbon) as analytical column with 0.1Macetic acid pH 2.8 and 30% acetonitrile as mobile phase. The calibration graph was linear (r2= 0.9999) and the detection limits were in the low picomole (UV) or femtomole (fluorescence) range. Optimization of the analytical column revealed that elution order and selectivity for the glucuronides were dependent on the buffer agent and temperature used. By appropriate choice of mobile phase conditions all four diastereomers could be separated. © 1992 Wiley‐Liss

ISSN:0899-0042    

DOI:10.1002/chir.530040809

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

摘要:

AbstractThe indirect chiral separation of the four stereoisomers (1)‐‐(4) of a novel carbonic anhydrase inhibitor with two chiral centers in the molecule is reported. The method is based on chemical derivatization of the secondary amino group of the inhibitor with chiral isocyanate, formation of diastereomeric urea derivatives, each with three chiral centers in the molecule, and their separation under nonchiral HPLC conditions. The attempts to separate racemic mixture (1)+(2) from its diastereomeric counterpart (3)+(4) under nonchiral conditions, and to separate enantiomers (1) and (2) directly on a chiral stationary phase (CSP) are also reported. The indirect method was utilized for the assessment of an in vivo inversion of configuration at either one or both chiral centers of the molecule of (1). Analyses of selected whole blood and urine samples from human subjects after multiple bilateral topical ocular dosing with (1) did not reveal the presence of any of the three possible stereoisomers (2)‐‐(4) of (1) indicating that the inversion of configuration at neither one nor two chiral centers of (1) occurs in vivo. © 1992 Wiley

ISSN:0899-0042    

DOI:10.1002/chir.530040810

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY

ISSN:0899-0042    

DOI:10.1002/chir.530040811

出版商:Alan R. Liss, Inc.    

年代:1992

数据来源: WILEY