Preclinical pharmacological actions of (+/-)-(1'R,3R)-3-phenyl-1- [1',2',3',4'-tetrahydro-5',6'-methylene-dioxy-1'-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200), a potential antidepressant agent that antagonizes alpha-2 adrenergic receptors and inhibits the neuronal uptake of norepinephrine

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 272; no. 3; p. 1160
• Main Authors: Hancock, A A, Buckner, S A, Giardina, W J, Brune, M E, Lee, J Y, Morse, P A, Oheim, K W, Stanisic, D S, Warner, R B, Kerkman, D J
• Format: Journal Article
• Language: English
• Published: United States 01-03-1995
• Subjects: Adrenergic alpha-2 Receptor Antagonists; Adrenergic Uptake Inhibitors - pharmacology; Animals; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Blood Pressure - drug effects; Clonidine - pharmacology; Guinea Pigs; Heart Rate - drug effects; Hippocampus - metabolism; In Vitro Techniques; Male; Motor Activity - drug effects; Mydriasis - chemically induced; Neurons - metabolism; Olfactory Bulb - physiology; Pyrrolidines - pharmacology; Rabbits; Radioligand Assay; Rats; Rats, Sprague-Dawley; Synaptosomes - metabolism; Tyramine - analogs & derivatives; Tyramine - pharmacology
• ISSN: 0022-3565

(+/-)-(1'R*,3R*)-3-phenyl-1-[(1',2',3',4'-tetrahydro-5',6'-methylene- dioxy-1'-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) was evaluated in a number of biological tests to establish its pharmacological profile of activity. ABT-200 antagonized the uptake of [3H]-norepinephrine into synaptosomes of rat hypothalamus (IC50 = 841 nM) and blocked 4,alpha-dimethyl-m-tyramine- induced hypermotility in rats. In addition, ABT-200 potently inhibited binding of [3H]-rauwolscine to alpha-2 adrenergic receptors with a Ki value in radioligand binding assays of approximately 1 nM in the rat cortex and was much less potent at other receptor binding sites. ABT-200 antagonized alpha-2 receptors in vitro in the rat vas deferens and dog saphenous vein, where pA2 values of 7.7 and 8.2, respectively, were obtained. ABT-200 also antagonized clonidine-induced mydriasis and increased the overflow of [3H]-norepinephrine in guinea pig hippocampal slices, manifestations of blockade of alpha-2 adrenoceptors in the central nervous system. ABT-200 was active in antagonizing nocturnal hyperactivity in olfactory bulbectomized rats, a test for putative antidepressant activity. In cardiovascular studies, ABT-200 exhibited negligible activity in affecting hemodynamic parameters and was free of postural hypotensive activity. In both in vitro and in vivo, ABT-200 was devoid of antihistaminic or anticholinergic activity. This profile of activity of moderate inhibition of norepinephrine uptake with blockade of alpha-2 adrenoceptors suggests potential dual-action effects for ABT-200, which may represent a putative antidepressant with minimal cardiovascular side-effect liability.