Interactions of flerobuterol, an antidepressant drug candidate, with beta adrenoceptors in the rat brain.

Interactions of dl-flerobuterol with central beta adrenoceptors were investigated. It inhibited the binding of 3H]CGP 12177, a selective beta adrenoceptor ligand, to membranes prepared from rat cerebral cortex, cerebellum, heart and lung. The affinity of dl-flerobuterol was very close in all tissues (Ki approximately 1 microM). In cerebral cortex, binding inhibition of 3H]CGP 12177 was stereospecific, l-flerobuterol (Ki = 483 nM) being 70-fold more potent than d-flerobuterol (Ki = 34 microM). Moreover, dl-flerobuterol (Ki = 926 nM) was 7-fold less potent than isoproterenol (Ki = 140 nM) to displace 3H]CGP 12177 binding, but 5-fold more potent than salbutamol (Ki = 4600 nM). Flerobuterol did not inhibit the radioligand binding to the other receptors at the highest concentration tested, thus leading to a very high beta adrenergic selectivity. Flerobuterol increased the concentration of cyclic AMP in slices of rat cerebral cortex in a dose-dependent manner; this effect was antagonized by atenolol and propranolol. Compared to isoproterenol or norepinephrine, which produced cyclic AMP maximal increases of 380 and 460%, respectively, it showed a weaker activity with a maximal stimulation obtained at 100 microM, corresponding to a cAMP increase of 140% over basal value (100%). These data revealed that flerobuterol possessed a beta adrenergic agonist activity. Moreover, it antagonized competitively the isoproterenol- or norepinephrine-stimulated accumulation of cAMP. At low concentrations of isoproterenol or norepinephrine, the stimulation of adenylate cyclase was only due to the action of flerobuterol, but at higher concentrations, the response of isoproterenol or norepinephrine was competitively blocked by flerobuterol. At 10 microM, isoproterenol surmounted fully this antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)