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Start Over Descriptor "5-HT3 receptors" Publisher springer-verlag
31 results on '"5-HT3 receptors"'

3. Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test.

Author

Iyer KA, Alix K, Eltit JM, Solis E Jr, Pan X, Argade MD, Khatri S, De Felice LJ, Sweet DH, Schulte MK, and Dukat M

Subjects
Animals, Antidepressive Agents pharmacology, Depression drug therapy, Depression psychology, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, HEK293 Cells, Hindlimb Suspension adverse effects, Humans, Locomotion drug effects, Locomotion physiology, Male, Mice, Mice, Inbred ICR, Quinazolines pharmacology, Serotonin Antagonists pharmacology, Xenopus laevis, Antidepressive Agents chemistry, Antidepressive Agents therapeutic use, Hindlimb Suspension psychology, Quinazolines chemistry, Quinazolines therapeutic use
Abstract

Rationale: 2-Amino-6-chloro-3,4-dihydroquinazoline (e.g., A6CDQ) represents a novel putative antidepressant originally thought to act through a 5-HT 3 serotonin receptor antagonist mechanism. Here, we investigated this further by examining a positional isomer of A6CDQ (i.e., A7CDQ)., Materials and Methods: 5-HT 3 receptor and transporter activity (uptake-1 and uptake-2) were investigated using a variety of in vitro assays and the in vivo mouse tail suspension test (TST)., Results: Although A7CDQ binds at 5-HT 3 receptors with low affinity (K i  = 1975 nM) compared to A6CDQ (K i  = 80 nM), it retained 5-HT 3 receptor antagonist action (IC 50  = 5.77 and 0.26 μM, respectively). In the mouse TST A7CDQ produced antidepressant-like actions (ED 50  = 0.09 mg/kg) comparable to that of A6CDQ. In addition, A6CDQ was found to be a 5-HT releasing agent (K m  = 2.8 μM) at hSERT and a reuptake inhibitor (IC 50  = 1.8 μM) at hNET, whereas A7CDQ was a weak reuptake inhibitor (K m  = 43.6 μM) at SERT but a releasing agent (EC 50  = 3.3 μM) at hNET. Moreover, A6CDQ and A7CDQ were potent inhibitors of uptake-2 (e.g.; OCT3 IC 50  = 3.9 and 5.9 μM, respectively)., Conclusions: A simple shift of a substituent in a common quinazoline scaffold from one position to another (i.e., a chloro group from the 6- to the 7-position) resulted in a common action in the TST but via a somewhat different mechanism. A6CDQ and A7CDQ might represent the first members of a new class of potential antidepressants with a unique multi-modal mechanism of action.

Published
2019
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