Pharmacological characterization of abbott-81282, a novel, non-peptide angiotensin-II antagonist selective for type-1 receptors

Hancock, Arthur A.; Buckner, Steven A.; Lee, J.Y.; Brune, Michael E.; Morse, Patricia A.; Oheim, K.; Warner, Robert B.; Winn, Martin; Zydowsky, Thomas M.; De, Biswanath; Kerkman, Daniel J.; DeBernardis, John F.

doi:10.1016/0024-3205(93)90445-9

Cited by 3 publications

(1 citation statement)

References 9 publications

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“…Clonidine-induced mydriasis was measured in rats as previously described by Berridge et al [1983] and Hancock et al [1995b]. Iloses of 60, 100, o r 300 prnoles/kg, po, of A-80426, 60 or 100 pnioleskg, po, of the reference cxu,-antagonist, rauwolscine, or vehicle (50% hydroxypropyl p cyclodextrin), were administered to rats (225-250 g) 30 min before the c h i d i n e challenge.…”

Section: Clonidine-induced Mydriasismentioning

confidence: 99%

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

Giardina

Buckner

Brune

et al. 1995

Drug Development Research

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A-80426 (N-L2-(benzofuran-6-yl)ethyl]-N-[(R)-( +)-5-methoxy-I ,2,3,4-tetrahydronaphthalen-I-yl methyl]-N-methylamine)is a compound that combines in vitro selective inhibition of serotonin synaptosomal uptake and or,-adrenoceptor antagonism In the present studies, A-80426 was evaluated in vivo for its ability to block serotonin uptake and a,-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 (ED, , = 13 pmolesikg, Po) and chronic (14 day) (ED, , = 4 1 pmolesikg, po) dosing At doses of 6.7 and 22 pnolesikg, po, A-80426 was effective in this test procedure for at least 12 h following administration. Doses of 6.7 to 224 pmolesikg, ip, of A-80426, however, failed to block hypothermia and hypoactivity produced by the a,-adrenoceptor agonist clonidine, and doses of 100 and 300 pnoles/kg, PO, were required to blocked clonidine-induced mydriasis. Thus, the in vitro orL 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 (ED, , = 7.1 pmolesikg, 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 pmoles/kg, ip. In contrast, fluoxetine was active in all three paradigms.

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Section: Clonidine-induced Mydriasismentioning

confidence: 99%

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

Giardina

Buckner

Brune

et al. 1995

Drug Development Research

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[3H]A-81988, a potent, selective, competitive antagonist radioligand for angiotensin AT1 receptors

Hancock

Surber

Rotert

et al. 1994

European Journal of Pharmacology: Molecular Pharmacology

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Receptor Interactions of Abbott-81988, A Highly Potent, Non-Peptide Angiotensin-II Antagonist Selective for Type-1 Receptors

Hancock

Buckner²,

Lee³

et al. 1994

Journal of Receptor Research

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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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Pharmacological characterization of abbott-81282, a novel, non-peptide angiotensin-II antagonist selective for type-1 receptors

Cited by 3 publications

References 9 publications

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

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

[3H]A-81988, a potent, selective, competitive antagonist radioligand for angiotensin AT1 receptors

Receptor Interactions of Abbott-81988, A Highly Potent, Non-Peptide Angiotensin-II Antagonist Selective for Type-1 Receptors

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Pharmacological characterization of abbott-81282, a novel, non-peptide angiotensin-II antagonist selective for type-1 receptors

Cited by 3 publications

References 9 publications

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

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

[3H]A-81988, a potent, selective, competitive antagonist radioligand for angiotensin AT1 receptors

Receptor Interactions of Abbott-81988, A Highly Potent, Non-Peptide Angiotensin-II Antagonist Selective for Type-1 Receptors

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Product

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

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