ISSN:0899-0042    

DOI:10.1002/chir.530020402

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractIf diastereomeric complexes are adsorbed on a surface or if they include a molecule of solvent, two points of attractive interaction between the chiral species of the complex can be sufficient for mutual chiral recognition of these species. In special cases even one single point of interaction is sufficient. This extension of the three‐point contact rule of Dalgliesh, first observed in chiral ligand‐exchange chromatogrphy, can be demonstrated by using ha

ISSN:0899-0042    

DOI:10.1002/chir.530020403

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractRecently published data1on the aftinities of 14 pairs of chiral ligands, (1,3‐oxathiolanes) for muscarinic receptors in three different tissues were subjected toeudismic analysesTheenantiomericeudismic‐affinity correlations (EACs) found by Gualtieri et al.1were confirmed and extended to the submolecular level: (1) regressions of the eudismic index (log affinity ratio; EI) against eutomer potency of the average affinities were highly significant, indicating that the binding sites in all three tissues are identical; (2) for the five agonists the EAC was shifted to lower affinities and had a small slope (EAQ), in agreement with previous observations in other systems; (3) of the nine antagonists, six gave an excellent regression with unit slope, practically superimposable on that previously obtained for 10 structurally different oxotremorine derivatives, while two others (1,3‐oxathiolanes) could be plotted on a separate line with the same EAQ, but shifted to higher affinities; (4) the aberrant low EI of the last antagonist could be explained in terms of its structureFurthermore, anepimericEAC (EEAC) revealed additional important information for quantitative stereo‐structure–activity relationships (QSSAR): the 25 possible epimeric comparisons were found to group into 6 different EACs in accord with differences in their structure: (1) the agonists fell on three separate lines of nearly identical (unitary) slope, which grouped cleanly in terms of the center of epimerization (positions 2, 3, and 5); (2) the antagonists of lower affinity fell on three lines with a commonX‐intercept but with different slopes corresponding to epimerization at the different centers of chirality, indicating that these displayquantitative differences in their criticalitytoward stereoselective recognition; (3) the remaining two antagonists of higher affinity fell on a separate line, again of unit slope.The significance of these correlations is discussed in relation to receptorspeciationand in regard to other stereoselectivity data available on muscarinic receptorsThe quantitation of thecriticalityof different chiral centers, made possible here by the very high binding energies involved, should also be applicable to other stereoselective recognition processes (e.g., in enantioselective chromatography). Finally, a fundamental assumption of molecular pharmacology and QSAR, i.e., that a given structural feature always contributes a constant amount to the overall binding energy, is questioned in view of the above findings, which indicate that the contributionincreaseswith the overall affinity, a feature which might be applicable to all pharmaca, not just to those containing chira

ISSN:0899-0042    

DOI:10.1002/chir.530020404

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractFenoldopam (SK&F 82526) is a potent and selective dopamine DA‐1 agonist with demonstrated renal vasodilator and antihypertensive activities in experimental animals and humans. Fenoldopam is a racemic mixture of two enantiomers, SK&F R‐82526 and SK&F S‐82526. The R‐enantiomer is uniformly reported to be more potent than the racemate; in contrast, there is controversy regarding potency of the S‐enantiomer. In these studies, the renal and systemic hemodynamic activities of fenoldopam and its enantiomers are characterized in anesthetized, phenoxybenzamine‐treated dogs. The results show that the renal and systemic vasodilator activities of fenoldopam are properties of the R‐enantiomer; the S‐enantiomer is essentially inactive. The renal and systemic vasodilator properties of SK&F R‐82526 are antagonized in a competitive fashion by the DA‐1 antagonist, SK&F R‐83566, but not the DA‐2 antagonist, domperidone. Ganglionic blockade did not attenuate renal vasodilation associated with SK&F R‐82526. Thus, the mechanism of SK&F R‐82526‐associated vasodilation, like that previously established for fenoldopam, is via stimulation of

ISSN:0899-0042    

DOI:10.1002/chir.530020405

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe effect of the enantiomers of a novel 5‐HT2receptor antagonist, (±)‐(1R,3S)‐1‐[2‐[4‐[3‐(p‐fluorophenyl)‐1‐indanyl]‐piperazinyl]ethyl]–2‐imidazolidinone, was studied on serotonin (5‐HT), noradrenaline (NA), potassium (K+), and calcium (Ca2+)‐induced contractions in isolated rat thoracic aorta. The enantiomers shifted the 5‐HT, NA, K+, and Ca2+concentration–response curves to the right in a concentration‐dependent manner and depressed the maximal contractile responses. The (+)‐enantiomer was a far more potent inhibitor of 5‐HT‐induced contractions than the (−)‐enantiomer. The (+)‐enantiomer and phentolamine, both at 10−6M, had equal inhibitory effects on NA‐evoked contractions. The (+)‐enantiomer was again more potent in inhibiting NA‐induced contractions than the (−)‐enantiomer. Both enantiomers had an equieffective inhibitory effect on K+and Ca2+‐induced contractions. The results show that the 5‐HT and α‐adrenoceptor antagonism of the two enantiomers is stereoselective, the (+)‐enantiomer being more potent than the (−)‐enantiomer. In contrast the enantiomers had equal

ISSN:0899-0042    

DOI:10.1002/chir.530020406

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

Abstract1H nuclear magnetic resonance at 360 MHz shows that SK&F 96365 (1‐{β‐[3‐(p‐methoxyphenyl)‐propyloxy]‐p‐methoxyphenethyl}‐1H‐ imidazole hydrochloride), an antagonist of mammalian receptor‐operated calcium channels, interacts with the calcium‐binding regulatory protein calmodulin (CaM). This may be inferred by a number of chemical shift changes in the spectrum of the calcium‐saturated protein induced by addition of the compound. Moreover, two well‐resolved singlets corresponding to the 2‐proton of the SK&F 96365 imidazolium moiety are observed in the spectrum over a wide range of protein:compound ratios. Separation ofracSK&F 96365 into its two enantiomers by high‐performance liquid chromatography on a cellulosetris(4‐methylbenzoate) column enabled us to show that the doubling of this NMR signal in the presence of CaM is due to a propensity of the protein to distinguish between the two

ISSN:0899-0042    

DOI:10.1002/chir.530020407

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe biological activity of the (+)‐S‐ and (−)‐R‐enantiomers of niguldipine, of the (−)‐S‐ and (+)‐R‐enantiomers of felodipine and nitrendipine, and of rac‐nisoldipine and rac‐nimodipine was investigated in vitro and in vivo. Inhibition of coronary vasoconstriction due to the thromboxane A2(TxA2)‐mimetic U‐46619 in guinea pig Langendorff hearts, displacement of (+)‐[3H]isradipine from calcium channel binding sites of guinea pig skeletal muscle T‐tubule membranes, and blood pressure reduction in spontaneously hypertensive rats were determined. The enantiomers were obtained by stereoselective synthesis. Cross‐contamination was<0.5% for both S‐ and R‐enantiomers of niguldipine and nitrendipine and<1% for those of felodipine. From the doses necessary for a 50% inhibition of coronary vasoconstriction, stereoselectivity ratios for (+)‐(S)‐/(−)‐(R)‐niguldipine, (−)‐(S)‐/(+)‐(R)‐felodipine, and (−)‐(S)‐/(+)‐(R)‐nitrendipine of 28, 13, and 7, respectively, were calculated. The potency ratio racnisoldipine/rac‐nimodipine was 3.5. Ratios obtained from binding experiments and antihypertensive activity were (+)‐(S)‐/(−)‐(R)‐niguldipine = 45 and 35, (−)‐(S)‐/(+)‐(R)‐felodipine = 12 and 13, (−)‐(S)‐/(+)‐(R)‐nitrendipine = 8 and 8, and rac‐nisoldipine/rac‐nimodipine = 8 and 7, respectively. Highly significant correlations were found between the in vitro potency of the substances to prevent U‐46619‐induced coronary vasoconstriction and their affinity for calcium channel binding sites as well as their antihypertensive activity. The mechanism of TxA2‐induced coronary vasoconstriction in guinea pig Langendorff hearts can be readily explained by a transmembrane influx of

ISSN:0899-0042    

DOI:10.1002/chir.530020408

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractStudies to characterize the pharmacokinetics of the enantiomers of MDMA were conducted in rats using the iliac arterial cannulation. Two routes of administration, intravenous and subcutaneous, were evaluated at two dose levels for each route [20 and 40 mg/kg (±)‐MDMA for subcutaneous, 10 and 20 mg/kg (±)‐MDMA for intravenous administrations]. The average half‐life (±SD) for all dosing groups was 2.5 ± 0.8 h for (−)‐(R)‐MDMA and 2.2 ±0.8 h for (+)‐(S)‐MDMA. The more rapid clearnace of (+)‐(S)‐MDMA compared with (−)‐(R)‐MDMA is consistent with the area under the curve (AUC) data of the parent drug and its primary metabolite MDA. The mean (±SD) AUC S/R ratios of MDMA and MDA were 0.70 ± 0.05 and 3.1 ± 0.8, respectively. Following a 20 mg/kg dose of racemic MDMA iv the mean (±SD) of the percent dose excreted as (−)‐(R)‐MDMA, (+)‐(S)‐MDMA, (−)‐(R)‐MDA, and (+)‐(S)‐MD

ISSN:0899-0042    

DOI:10.1002/chir.530020409

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe plasma disposition of the enantiomers of ibuprofen has been investigated following the oral administration of the racemic drug (400 mg) to 24 healthy male volunteers. The plasma elimination of (R)‐ibuprofen was found to be more rapid than that of the S‐enantiomer [plasma half‐life: (R) 2.03 h; (S) 3.05 h; 2P<0.001], resulting in a progressive enrichment in the plasma content of this isomer, some 64% of the total area under the plasma concentration time curves (AUC) being due to the pharmacologically active enantiomer. The influence of dose on the pharmacokinetic characteristics of the enantiomers of ibuprofen, over the range 200–800 mg, was investigated in three subjects. Examination of dosenormalized AUC values and oral clearance indicate the dose dependence of (R)‐ibuprofen di

ISSN:0899-0042    

DOI:10.1002/chir.530020410

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe enantioselective protein binding of mephobarbital (MPB) was investigated in human plasma and human serum albumin solutions by equilibrium dialysis. A small but statistically significant difference was observed in the in vitro plasma protein binding of the enantiomers; (S)‐MPB was ∼59% bound and (R)‐MPB ∼67% bound. The binding to albumin [(S)‐MPB: ∼29% bound, and (R)‐MPB: ∼41% bound] was less than to plasma proteins but showed somewhat greater enantioselectivity, suggesting that albumin binding is a major source of the enantioselectivity in plasma. The effects of MPB concentration, of varying enantiomeric concentration ratio, and of phenobarbital on the enantioselective binding of MPB were studied. The effect of age was also investigated by measuring the binding in plasma from 8 young (18–25 yr) and 8 elderly (>60 yr) male subjects who took single doses of MPB. The results were in close agreement with the in vitro binding data, and the binding of both enantiomers was marginally but significantly lower in the young compared with the elderly subjects. These differences in binding were consistent with previously observed pharmacokinetic differences between the t

ISSN:0899-0042    

DOI:10.1002/chir.530020411

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY