title: Alkylating beta-blockers: activity of isomeric bromoacetyl alprenolol menthanes.
abstract: An affinity label for beta-adrenoceptors, N-(bromoacetyl)-N'-[3-(o-allylphenoxy)-2-hydroxypropyl]-1,8-dia min o-p-menthane, has been extensively used in the form of a mixture of four isomers. In the present study, all four isomers were isolated, their structures elucidated, and their interactions with beta-adrenoceptors characterized. The isomer with the aromatic (pharmacophore) group on carbon 1 of p-menthane and with the Z configuration (Z-1) predominates in the mixture and has the highest affinity for beta-adrenoceptors of rat heart (KD = 3 X 10(-8) M) and lungs (KD = 2 X 10(-8) M). This isomer acts as a ligand that binds irreversibly at the drug binding site of the receptor (i.e., after treatment and extensive washing of the membrane preparation, the concentration of the receptors is decreased in a dose-dependent manner), while binding characteristics of the remaining receptors are not changed. The corresponding E diastereomer (E-1) also binds irreversibly to the drug binding site of the receptor. The isomer with the aromatic group on carbon 8 and the Z configuration (Z-8) modifies the receptor noticeably only at higher concentrations and then on a site apparently different from the drug-binding site, i.e., affinity of receptors after the treatment and washing is changed. The corresponding E diastereomer (E-8) modified both the drug-binding and alternative binding site. The results suggest that there is some flexibility in the conformation of the beta-adrenoceptor that enables pairs of ligands, differing by axial or equatorial positions of critical groups, to alkylate the receptor in an analogous manner.
authors.forename: A
authors.initials: A
authors.lastname: Liptak
authors.forename: J W
authors.initials: JW
authors.lastname: Kusiak
authors.forename: J
authors.initials: J
authors.lastname: Pitha
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000345:Affinity Labels / Q000378:metabolism; D000526:Alprenolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004082:Dihydroalprenolol / Q000378:metabolism; D007536:Isomerism; D008168:Lung / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000319:Adrenergic beta-Antagonists; D000345:Affinity Labels; D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; C045331:bromoacetylalprenololmenthane; D000526:Alprenolol