摘要:

AbstractThe QSAR for forty 2,4‐diamino‐5‐(X‐benzyl)‐pyrimidines inhibiting human lymphoblastoid dihydrofolate reductase is reported and compared with the QSAR for inhibition of dihydrofolate reductase fromE. coli, L. casei, chicken, and bovine liver sources by the same inhibitors. A preliminary attempt to integrate the experimental QSAR results with the three‐dimensional X‐ray structures ofE. coliand chicken dihydrofolate reductase, using interactive computer three‐dimensional color graphics molecular modeling method

ISSN:0931-8771    

DOI:10.1002/qsar.19820010102

出版商:WILEY‐VCH Verlag    

年代:1982

数据来源: WILEY

摘要:

AbstractCentral hypotensive activity of α‐adrenoceptor agonists generally parallels bradycardic potency. This has led to the conclusion that bradycardia, like the induction of hypotension, is also initiated within the central nervous system by stimulation of α2‐adrenoceptors. However, bradycardia has still been found for a very hydrophilic α‐adrenoceptor agonist not showing central hypotensive activity following systemic application. In view of this inconsistency quantitative comparisons were made between central hypotensive activity and overall bradycardic potency in anaesthetized normotensive rats after intravenous administration within a series of phenyliminoimidazolidines. The log dose‐bradycardic response curves of the more lipophilic derivatives were monophasic, whereas those of the hydrophilic compounds were characterized by a bisigmoidal shape. As a result of the dual nature of this effect, the potency of the drugs to decrease heart rate was quantified at 10%, pC10(HR), as well as at 20%, pC20(HR), effect level. Linear regression analysis showed a highly significant correlation between pC20(HR) and hypotensive activity. Lipophilicity, log P′, had to be added to verify this relationship for pC10(HR). For the latter variable, however, a linear relationship was derived with the potency of the compounds to inhibit cardiac frequency via stimulation of presynaptic α2‐adrenoceptors in the heart itself. These results strongly suggest that overall bradycardia of α‐adrenoceptor agonists may consist of a peripheral and a central component. Both mechanisms are governed by the stimulation of α2‐adrenoceptors. The peripheral mechanism (presynaptic cardiac α2‐adrenoceptors) is triggered by hydrophilic as well as lipophilic compounds following systemic application. The induction of central bradycardia (central α2‐adrenoceptors) and hypotension is but limited t

ISSN:0931-8771    

DOI:10.1002/qsar.19820010103

出版商:WILEY‐VCH Verlag    

年代:1982

数据来源: WILEY

摘要:

AbstractObserved rates of absorption of drugs by passive diffusion through lipid membranes depend on certain physicochemical properties of the drug being absorbed and of the lipid barrier to be penetrated. By combining the pH partition theory, the unstirred layer hypothesis, and LFE considerations several model equations were derived. Within congeneric series of acidic or basic compounds these equations allow one to quantitatively describe the nonlinear dependence of the rate of absorption on lipophilicity and degree of ionization as well as to explain the observation of pH shifts in pH absorption profiles of drugs. Generally an excellent fit of the equations to observed rate constants for several classes of compounds was obtained. Furthermore some indications are presented that absorption rates are influenced by aqueous as well as by lipid stagnant diffusion layers adjacent to the aqueous/lipid interface.

ISSN:0931-8771    

DOI:10.1002/qsar.19820010104

出版商:WILEY‐VCH Verlag    

年代:1982

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19820010105

出版商:WILEY‐VCH Verlag    

年代:1982

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19820010101

出版商:WILEY‐VCH Verlag    

年代:1982

数据来源: WILEY