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: V Homburger, H Gozlan, R Bouhelal, M Lucas, J Bockaert
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 328 Issue 3 Pg. 279-87 (Jan 1985) ISSN: 0028-1298 [Print] Germany
• PMID: 2858822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Receptors, Adrenergic, beta
• Dihydroalprenolol
• Br-AAM-pindolol
• Pindolol
• Adenylyl Cyclases
• Isoproterenol

Topics

• Adenylyl Cyclases (analysis)
• Adrenergic beta-Antagonists (metabolism, pharmacology)
• Animals
• Dihydroalprenolol (metabolism)
• Erythrocytes (drug effects)
• Glioma (metabolism)
• In Vitro Techniques
• Isoproterenol (metabolism)
• Pindolol (analogs & derivatives, metabolism, pharmacology)
• Rats
• Receptors, Adrenergic, beta (drug effects)