title: Irreversible blockade of beta-adrenergic receptors with a bromoacetyl derivative of pindolol.
abstract: A potent irreversible beta-adrenergic derivative of pindolol possessing a chemically reactive group (Br-AAM-pindolol) was synthesized. This compound devoid of agonist properties, competed for all (3H)-dihydroalprenolol (3H-DHA) binding sites in C6 glioma cell and rat cerebellum membranes. Pretreatment of C6 glioma cell membranes with Br-AAM-pindolol and subsequent washing resulted in a time- and dose-dependent blockade of beta-adrenergic receptors. A 50% blockade was achieved in the presence of 1.6 nM Br-AAM-pindolol. This blockade occurs specifically at the beta-adrenergic receptor level, as: 1) it induced a decrease of maximal isoproterenol stimulated adenylate cyclase activity with no modification of basal and sodium fluoride stimulated activity and 2) decreases of (3H)-DHA binding and stimulation of adenylate cyclase activity by the agonist were suppressed in the presence of isoproterenol, a beta-adrenergic agonist. Furthermore, Br-AAM-pindolol treatment did not affect (3H)-diazepam binding in C6 glioma cell membranes. Pretreatment of C6 glioma cells with Br-AAM-pindolol also reduced the response of adenylate cyclase to isoproterenol and the number of beta-adrenergic receptors. The blockade of beta-adrenergic receptors of C6 glioma cells by Br-AAM-pindolol was non-competitive, whereas the blockade obtained with AM-pindolol, a derivative of pindolol devoid of alkylating properties, was competitive. The irreversible blockade of beta-adrenergic receptors by Br-AAM-pindolol in rat erythrocyte membranes was substantiated by the demonstration that no recovery of beta-adrenergic receptors occurred during long term incubation of the membranes (48 h) following Br-AAM-pindolol treatment and subsequent washing.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: V
authors.initials: V
authors.lastname: Homburger
authors.forename: H
authors.initials: H
authors.lastname: Gozlan
authors.forename: R
authors.initials: R
authors.lastname: Bouhelal
authors.forename: M
authors.initials: M
authors.lastname: Lucas
authors.forename: J
authors.initials: J
authors.lastname: Bockaert
mesh_terms: D000262:Adenylyl Cyclases / Q000032:analysis; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004082:Dihydroalprenolol / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects; D005910:Glioma / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000378:metabolism; D010869:Pindolol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; C044649:Br-AAM-pindolol; D010869:Pindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol