Drugs online research references
J Pharmacol Exp Ther. 1988 Apr;245(1):94-101.
Stereospecificity of beta adrenergic antagonists: R-enantiomers show increased selectivity for beta-2 receptors in ciliary process.
Nathanson JA.
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
The (+)-stereoisomers of arylethanolamine beta adrenergic agonists and antagonists are usually much less active in biological systems than their corresponding (-)-forms. In the eye, however, prior physiological studies have shown that these (+)-stereoisomers are unexpectedly potent in altering intraocular pressure, results which could be due to a difference in distribution and metabolism or to a difference in receptor interaction. The present experiments evaluated six stereoisomeric pairs of beta adrenergic antagonists for their ability to block rabbit ciliary process and cardiac beta adrenergic receptors activating adenylate cyclase, in vitro, under conditions in which the effects of drug metabolism, distribution and membrane lipid solubility were minimized. In the heart, all six pairs of antagonists demonstrated the expected increased potency of (-)-forms, with isomeric activity ratios of: 33 for metoprolol, 44 for timolol; 48 for bunitrolol; 76 for t-butyl-betaxolol; 100 for t-butyl-didesmethyl-ICI-118,551; and 530 for betaxolol. Under identical assay conditions in the ciliary process, (+)-enantiomers were much more potent relative to (-)-forms, with isomeric activity ratios of: 0.82 for timolol; 3.3 for bunitrolol; 7.4 for t-butyl-didesmethyl-ICI-118,551; 10 for metoprolol; 16 for t-butyl-betaxolol; and 190 for betaxolol. With the exception of metoprolol, all (+)-enantiomers demonstrated a substantially higher absolute affinity for ciliary process receptors (known to be almost exclusively of the beta-2 subtype) than for cardiac receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2896241&dopt=Abstract
Pharm Res. 1995 Dec;12(12):2053-6.
Regioselectivity and enantioselectivity of metoprolol oxidation by two variants of cDNA-expressed P4502D6.
Mautz DS, Shen DD, Nelson WL.
Department of Anesthesiology, University of Washington, Seattle 98195, USA.
PURPOSE: The oxidative metabolism of metoprolol was investigated in two human lymphoblastoma cell-lines transfected with variants of cDNA for cytochrome P4502D6. METHODS: The regioselective and enantioselective features of the oxidations of deuterium-labeled pseudoracemic metoprolol were characterized by GC/MS analysis of the substrate and products. RESULTS: There were significant differences between the two P4502D6 variants in the formation kinetics of O-demethylmetoprolol and alpha-hydroxymetoprolol. The h2D6-Val microsomes highly favored the formation of the O-demethylmetoprolol regioisomer 6.3:1 and 2.8:1, respectively from (R)-metoprolol-d0 and (S)-metoprolol-d2, while the corresponding ratios for h2D6v2 microsomes were much lower. For both variants, O-demethylmetoprolol formation favored the (R)-substrate 1.5 to 2-fold, while alpha-hydroxymetoprolol formation was non-enantioselective. Similar Km values of metoprolol oxidation, 10-20 microM, were observed for the two microsomal preparations. CONCLUSIONS: The regioselectivity, enantioselectivity, and Km values for the h2D6-Val microsomes resemble those observed for the native P4502D6 in human liver microsomes, whereas the h2D6v2 microsomes deviated remarkably in regioselectivity.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8786988&dopt=Abstract
J Chromatogr A. 1999 Oct 1;857(1-2):107-15.
Discrimination between enantioselective and non-selective binding sites on cellobiohydrolase-based stationary phases by site specific competing ligands.
Henriksson H, Pettersson G, Johansson G.
Department of Biochemistry, Uppsala University, Biomedical Centre, Sweden.
A systematic study was performed to investigate the influence of cellobiose or lactose on the enantioselective retention behaviour of some beta-blockers in liquid chromatography using Cellobiohydrolase (CHB) I from Trichoderma reesei or Cellobiohydrolase 58 from Phanerochaete chrysosporium immobilized on silica as stationary phases. The results revealed that the retention could be described by the function [equation; see text] where the observed capacity factor corresponds to the sum of an enantioselective mode being influenced by a site specific competing ligand (competitor) and a non-selective mode unaffected by the competitor. A non-constrained non-linear least-square regression gave in all cases virtually identical nondisplacable capacity factors (k'ns) for both enantiomers of the same drug. The experimental capacity factors (k'(x,C)) of the enantiomers all show a close fit to the adapted function. The Kd values calculated for the competitor were also virtually identical for each pair of enantiomers and were in accordance with Ki data determined for the competitors in classical enzyme kinetics experiments, demonstrating that one unique site; namely, the catalytic site, was responsible for the enantioselective binding. Similar results were obtained with the resolution of rac-alprenolol and rac-metoprolol on CBH I phase.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10536829&dopt=Abstract
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