Effects of JL 3, a putative antidepressant, on rat noradrenergic and serotonergic systems.
Using in vitro electrophysiological procedures, we confirm the inhibitory effect of 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1, 4]benzothiazepine (JL 3), on dorsal raphe serotonergic (IC(50)=14 microM) and noradrenergic neurons (IC(50)=4.5 microM). The effect on dorsal raphe neurons was reduced by N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- cyclohexanecarboxamide (WAY-100635), suggesting the importance of 5-HT(1A) receptor stimulation. Yohimbine, and ritanserin, to a lesser extent, blocked the inhibitory effect of JL 3 on locus coeruleus neurons indicating that alpha(2)-adrenoceptors and 5-HT(2A) receptors may be implicated in the effects. Because of its negligible alpha(2)-adrenoceptor affinity, the effect of JL 3 on locus coeruleus neurons, would have to be indirect. JL 3 may interfere with the norepinephrine transporter site (IC(50)=0.34 microM). JL 3 tended to reinforce the hypertensive effect of norepinephrine, while it strongly inhibited the hypertensive effect of tyramine, further indicating an interaction at the norepinephrine transporter site level.
Liégeois
J
J
Laboratory of Medicinal Chemistry, University of Liège, 1 avenue de l'Hôpital (B36), B-4000, Liège, Belgium. jf.liegeois@ulg.ac.be
Seutin
V
V
Scuvée-Moreau
J
J
Dresse
A
A
Bruhwyler
J
J
Géczy
J
J
Delarge
J
J
Damas
J
J
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D004347:Drug Interactions; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013841:Thiazepines / Q000494:pharmacology*; D014439:Tyramine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D013841:Thiazepines; C103197:10-(4-methylpiperazin-1-yl)pyrido(4,3-b)(1,4)benzothiazepine; D009638:Norepinephrine; D014439:Tyramine