A-80426 (N-[2-( benzofu ran-6-yl)ethyll-N-[(R)-( t )-5-methoxy-I ,2,3,4-tetrahydronaphthalen-1-yl methyl]-N-methylamine) i s a novel compound with potential antidepressant activity.A-80426 inhibits synaptosomal serotonin (5HT) uptake (lC5,) = 13 nM) more potently than fluoxetine (lCio = 308 nM), and blocks [3H]-paroxetine binding (K, = 3.8 nM) to 5HT uptake sites. A-80426 inhibits ['HI-rauwolscine binding to a,-adrenoceptors (K, = 2.0 nM), blocks a,-adrenoceptors (pEC,, = 7.4-7.5) in electrically stimulated rat atria and vas deferens, and increases electrically stimulated ['HI-NE overflow from brain slices. A-80426 lacks significant activity at isolated tissue models of a,-or p-adrenergic sites or at M, muscarinic or H , histaminergic receptors. A-80426 has negligible radioligand binding activity at 5HT, and P-adrenergic receptors, but exhibits a K, value of 144 n M at 5HT, receptors. A-80426 interacts with both dopamine D, (K, = 744 nM) and D, (K, = 51.5 nM) receptors. Functionally, the compound antagonizes dopamine-induced changes in cyclic A M P formation with K, values of 133 n M and 185 n M at D, and D, receptors, respectively. The potent a,-adrenoceptor blocking activity of A40426 in radioligand binding assays 15 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., 19951, while indicating activity in the olfactory bulbectomized rat model of antidepressant action, shows a marked reduction in the a,-antagonictic propertiec of A-80426 in other in vivo models, suggesting that the antideprescant-like activity may be caused primarily by inhibition of 5HT uptake.(0 1995 Wiley-Liss, Inc
