A‐80426, a potent and selective α2‐adrenoceptor antagonist with serotonin uptake‐blocking activity and putative antidepressant‐like effects: II. Pharmacology profile

Abstract

AbstractA‐80426 N‐[2‐(benzofuran‐6‐yl)ethyl]‐N‐[(R)−( + (‐5‐methoxy‐1,2,3,4‐tetrahydronaphthalen‐1‐yl methyl]‐N‐methylamine) is a compound that combines in vitro selective inhibition of serotonin synaptosomal uptake and α2‐adrenoceptor antagonism. In the present studies, A‐80426 was evaluated in vivo for its ability to block serotonin uptake and α2‐adrenoceptors. The antidepressant potential of the compound was also assessed.In rats, A‐80426 significantly reduced p‐chloroamphetamine (PCA)‐induced hyperactivity, a measure of the in vivo blockade of serotonin uptake, after acute (ED50 = 13 μmoles/kg, po) and chronic (14 day) (ED50 = 4.1 μmoles/kg, po) dosing. At doses of 6.7 and 22 μmoles/kg, po, A‐80426 was effective in this test procedure for at least 12 h following administration. Doses of 6.7 to 224 μmoles/kg, ip, of A‐80426, however, failed to block hypothermia and hypoactivity produced by the α2‐adrenoceptor agonist clonidine, and doses of 100 and 300 μmoles/kg, po, were required to blocked clonidine‐induced mydriasis. Thus, the in vitro α2 receptor binding and blocking effects observed with A‐80426 did not translate into the in vivo situation.A‐80426 was able to reverse the step‐down passive avoidance deficit seen in olfactory bulbectomized rats (ED70 = 7.1 μmoles/kg, po), a finding suggesting that the compound has antidepressant potential. The compound was, however, inactive in the tail suspension and forced swim tests of antidepressant activity in mice at doses up to 72 μmoles/kg, ip. In contrast, fluoxetine was active in all three paradigms.Despite its favorable in vitro profile, A‐80426 is not an effective α2 blocker in vivo and is inactive in the behavioral dispair models of depression. It is unlikely that A‐80426 would have antidepressant activity equivalent to existing selective serotonin reuptake inhibitors. α2 blockade as a potential approach to eliciting antidepressant activity is discussed. © 1995 Wiley‐Liss, Inc.