摘要:

AbstractLow temperature base catalyzed autoxidation (BCA) of the A‐ring of 21‐acetoxypregn‐5‐ene‐3,20‐dione 20‐ethylene ketal (7) resulted in the saponification of the ester with the concomitant formation of 2,21‐dihydroxypregna‐1,4‐diene‐3,20‐dione 20‐ethylene ketal (8) Continued BCA at ambient temperature, converts the latter to 1,21‐dihydroxy‐2‐oxaprogesterone 20‐ethylene ketal (9), which is reduced by NaBH4to the 2‐oxasteroid, 21‐hydroxy‐2‐oxaprogesterone 20‐ethylene ketal (10). Treatment of enol8, lactol9,9, and lactone 10 with aqueous acid generates the corresponding deprotected analogs 2,21‐dihydroxypregna‐1,4‐diene‐3,20‐dione (enol11), 1,21‐dihydroxy‐2‐oxaprogesterone (lactol12), and 2‐oxacortexone (2‐oxadesoxycorticosterone, 21‐hydroxy‐2‐oxaprogesterone, lactone13). In bovine spermatozoa, neither 2‐oxasteroid ketal10nor its deprotected analog13stimulated Ca2+uptake. In high concentration (0.5 mM), the inhibition of Ca2+uptake is only 37% for13, as compared to 83% found with the parent steroid, cortexone (desoxycorticosterone, 21‐hydroxyprogesterone,5). The difference in molecular structure between13and5indicates the importance of the oxygen atom in ring A in achieving the protective effect of the steroid. Ketalization of the C‐20 carbonyl is not important for protection. Thus it seems that by replacing C‐2 by an oxygen atom we can reduce the biological damage caused by relatively high concentrations of steroid treatment. These results are highly sig

ISSN:0365-6233    

DOI:10.1002/ardp.19973300502

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractMolecular modification of the potent and selective muscarinic antagonist 2‐ethylthio‐2,2‐diphenylacetic acidN,N‐diethylamino‐ethyl ester was performed in order to identify M2selective antagonists able to cross the blood brain barrier and potentially useful in the treatment of Alzheimer's disease. Modifications included substitution or hydrogenation of one of the phenyl rings as well as their incorporation in a tricyclic system. In general the changes introduced were detrimental for both affinity and selectivity. Only a modest M2selectivity is present in some compounds that, on the other hand, carry a quaternary ammonium group which precludes their penetration into

ISSN:0365-6233    

DOI:10.1002/ardp.19973300503

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractThe synthesis and glycine‐NMDA binding activity of a series of quinazoline‐2‐carboxylic acids1and quinazoline‐2,4‐diones2, containing all the essential and optional pharmacophoric descriptors required by a putative glycine antagonist model, are reported. The binding results show that only three of the title compounds displayed micromolar receptor affinity, demonstrating how disappointing the synthesis of receptor ligands based only on interaction mode

ISSN:0365-6233    

DOI:10.1002/ardp.19973300504

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractNine natural and synthetic estrogens, all derived from endogenous 17β‐estradiol, were tested for their affinity to cytochrome P‐450 (P450). Binding spectra of the estrogens with rat liver microsomal P450 and inhibition kinetics with characteristic monooxygenase model reactions (ethylmorphineN‐demethylation, EN, and ethoxycoumarinO‐deethylation, EO) were determined. In addition, uncoupling effects and/or free radical scavenger functions were analysed by NADPH/Fe++stimulated microsomal luminol‐and lucigenin‐amplified chemiluminescense (CL). 17β‐Estradiol, 17α‐ethynylestradiol, and D‐estradiol 3‐methyl ether inhibited both monooxygenase reactions of cytochrome P‐450, whereas L‐estradiol 3‐methyl ether inhibited EO only. 17β‐Estradiol, 17α‐ethynylestradiol, and D‐estradiol 3‐methyl ether seem to act as free radical scavengers. From the results both structure activity relationships could be established and data on possible interferences with drug metabolism obtained. The enantiomers D‐ and L‐estradiol 3‐methyl et

ISSN:0365-6233    

DOI:10.1002/ardp.19973300505

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractIn the challenge to develop potent inhibitors of aromatase for reducing the levels of estrogens, we found that azolyl‐substituted indoles inhibit aromatase activity. 3‐(1‐Azolylmethyl)‐1H‐indoles9–15and 3‐(1‐azolyl‐1‐phenylmethyl)‐1H‐indoles22–25were prepared, and tested on their ability to inhibit P450 arom. Analysis of the inhibitory effect exerted by several derivatives (11, 12, 22, and23) on microsomal aromatasein vitroactivity indicates that azolyl‐substituted indoles containing an imidazole moiety are more potent inhibitors than triazole derivatives. In the first series, the introduction of theN‐benzyl moiety has been found to enhance the inhibitory profile of these 3‐(1‐azolylmethyl)‐1H‐indole derivatives. The corresponding 4‐fluoro derivative12displays the highest inhibitory activity (IC50= 0.0718 μM) of all investigated compounds; thus,12is 258 times as potent as aminoglutethimide (AG). The presence of a chloro grouping inparaposition of the phenyl ring in compounds22and24exerts a positive effect only in the triazol‐1‐yl sub‐

ISSN:0365-6233    

DOI:10.1002/ardp.19973300506

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractPreparation and affinity to 5‐HT1Aand 5‐HT2Areceptors of new buspirone analogues7–17are reported. The compounds possess high to low affinity to 5‐HT1Aand moderate to low to 5‐HT2Areceptors. The crystal structures have been determined for compounds11, 12, 13, and14. For low affinity ligand (15) of 5‐HT1Areceptor conformational analysis was performed and compared with similar analyses performed for know high (buspirone1) and very high (WY‐48, 7232) affinity ligands of the receptor. Structure‐activity relationship is discussed for the affinity to 5‐HT1Areceptor. A three‐point pharmacophore explaining interactions of buspirone‐like molecules with the receptor bin

ISSN:0365-6233    

DOI:10.1002/ardp.19973300507

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

ISSN:0365-6233    

DOI:10.1002/ardp.19973300501

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY