Pharmacological properties of 403U76, a new chemical class of 5-hydroxytryptamine- and noradrenaline-reuptake inhibitor.
403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene- methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats. The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment. Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.
Ferris
R M
RM
Wellcome Research Laboratories, Department of Pharmacology, Research Triangle Park, NC 27709, USA.
Brieaddy
L
L
Mehta
N
N
Hollingsworth
E
E
Rigdon
G
G
Wang
C
C
Soroko
F
F
Wastila
W
W
Cooper
B
B
D006916:5-Hydroxytryptophan / Q000008:administration & dosage / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000494:pharmacology*; D001667:Binding, Competitive; D004285:Dogs; D004594:Electrophysiology; D005473:Fluoxetine / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013045:Species Specificity; D009435:Synaptic Transmission / Q000187:drug effects; D013747:Tetrabenazine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014828:Vocalization, Animal / Q000187:drug effects
D006916:5-Hydroxytryptophan; D018759:Adrenergic Uptake Inhibitors; D001592:Benzyl Alcohols; D005473:Fluoxetine; D016666:Fluvoxamine; D007099:Imipramine; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors; D013747:Tetrabenazine; C098110:403U76