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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

Abbott-81988 (A-81988) was selected from a series of related compounds as a highly potent and selective antagonist of angiotensin receptors. In the rabbit aorta, A-81988 exhibited a pA2 of 10.12 (+/- 0.08) vs. angiotensin-II, for type 1 receptors (AT1), and the antagonism appeared competitive. These results agreed with radioligand assays in which A-81988 inhibited the binding of [125I]-Sar1-Ile8-Angiotensin-II to rat liver membranes with a pKI of 9.12 (+/- 0.63). A-81988 was selective for AT1 receptors based on its lack of activity at other sites, such as aortic alpha 1 receptors. Moreover, A-81988 lacked affinity for AT2 receptors of bovine cerebellar membranes or for alpha or beta adrenergic receptors in binding assays. A-81988 lowered blood pressure significantly in vivo in renal artery-ligated rats at doses of 0.3 mg/kg administered either i.v. or p.o. The compound was rapidly and almost completely absorbed from the duodenum of anesthetized rats and demonstrated very low first-pass metabolism in the rat liver. These properties of selectivity toward and potency for antagonizing AT1 receptors, activity in lowering blood pressure in experimental animals, and favorable pharmacokinetic properties indicate that A-81988 should be a useful antihypertensive agent in man.

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