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.
(+/-)-(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.
Hancock
A A
AA
Abbott Laboratories, Pharmaceutical Products Division, Abbott Park, Illinois.
Buckner
S A
SA
Giardina
W J
WJ
Brune
M E
ME
Lee
J Y
JY
Morse
P A
PA
Oheim
K W
KW
Stanisic
D S
DS
Warner
R B
RB
Kerkman
D J
DJ
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D015878:Mydriasis / Q000139:chemically induced; D009474:Neurons / Q000378:metabolism; D009830:Olfactory Bulb / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000378:metabolism; D014439:Tyramine / Q000031:analogs & derivatives / Q000494:pharmacology
C092508:ABT 200; D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents; D011759:Pyrrolidines; C001047:4, alpha-dimethyl-3-tyramine; D003000:Clonidine; D014439:Tyramine