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Abstract

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.

A A Hancock, S A Buckner, W J Giardina, M E Brune, J Y Lee, P A Morse, K W Oheim, D S Stanisic, R B Warner and D J Kerkman
Journal of Pharmacology and Experimental Therapeutics March 1995, 272 (3) 1160-1169;
A A Hancock
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S A Buckner
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W J Giardina
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M E Brune
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J Y Lee
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P A Morse
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K W Oheim
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D S Stanisic
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R B Warner
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D J Kerkman
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Abstract

(+/-)-(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.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 272, Issue 3
1 Mar 1995
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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 recept…
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Abstract

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.

A A Hancock, S A Buckner, W J Giardina, M E Brune, J Y Lee, P A Morse, K W Oheim, D S Stanisic, R B Warner and D J Kerkman
Journal of Pharmacology and Experimental Therapeutics March 1, 1995, 272 (3) 1160-1169;

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Abstract

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.

A A Hancock, S A Buckner, W J Giardina, M E Brune, J Y Lee, P A Morse, K W Oheim, D S Stanisic, R B Warner and D J Kerkman
Journal of Pharmacology and Experimental Therapeutics March 1, 1995, 272 (3) 1160-1169;
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