A‐80426, a potent α2‐adrenoceptor antagonist with serotonin uptake blocking activity and putative antidepressant‐like effects: I. Biochemical 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 novel compound with potential antidepressant activity. A‐80426 inhibits synaptosomal serotonin (5HT) uptake (IC50 = 13 nM) more potently than fluoxetine (IC50 = 308 nM), and blocks [3H]‐paroxetine binding (K1 = 3.8 nM) to 5HT uptake sites. A‐80426 inhibits [3H]‐rauwolscine binding to α2‐adrenoceptors (K1 = 2.0 nM), blocks α2‐adrenoceptors (pEC30 = 7.4–7.5) in electrically stimulated rat atria and vas deferens, and increases electrically stimulated [3H]‐NE overflow from brain slices. A‐80426 lacks significant activity at isolated tissue models of α1‐ or β‐adrenergic sites or at M3 muscarinic or H1 histaminergic receptors. A‐80426 has negligible radioligand binding activity at 5HT1 and β‐adrenergic receptors, but exhibits a K1 value of 144 nM at 5HT2 receptors. A‐80426 interacts with both dopamine D1 (K1 = 744 nM) and D2 (K1 = 51.5 nM) receptors. Functionally, the compound antagonizes dopamine‐induced changes in cyclic AMP formation with K1 values of 133 nM and 185 nM at D1 and D2 receptors, respectively. The potent α2‐adrenoceptor blocking activity of A‐80426 in radioligand binding assays is not reflected in isolated tissue bioassays, and may thus have less functional consequence in determining the in vivo profile of the compound. Accompanying behavioral data [Giardina et al., 1995], while indicating activity in the olfactory bulbectomized rat model of antidepressant action, shows a marked reduction in the α2‐antagonistic properties of A‐80426 in other in vivo models, suggesting that the antidepressant‐like activity may be caused primarily by inhibition of 5HT uptake. © 1995 Wiley‐Liss, Inc.