期刊
NEUROPSYCHOPHARMACOLOGY
卷 33, 期 10, 页码 2303-2312出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.npp.1301646
关键词
quetiapine; N-Desalkylquetiapine; norepinephrine reuptake inhibitor; antidepressant; antipsychotic
资金
- Intramural NIH HHS Funding Source: Medline
- NIMH NIH HHS [R01MH57635, R01MH60451, UF1MH 082441, R01MH61887, N01MH32004] Funding Source: Medline
Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo[b,f][ 1,4] thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein - coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H-1 receptor and moderate affinities (10 - 100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT1A, 5-HT1E, 5-HT2A, 5-HT2B, 5-HT7 receptors, the alpha(1B)-adrenergic receptor, and the M-1, M-3, and M-5 muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT1D, 5-HT2C, 5-HT3, 5-HT5, 5-HT6, alpha(1A), alpha(2A), alpha(2B), alpha(2C), H-2, M-2, M-4, and dopamine D-1, D-2, D-3, and D-4 receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K-i of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT1A receptor. N-Desalkylquetiapine was an antagonist at 5-HT2A, 5-HT2B, 5-HT2C, alpha(1A), alpha(1D), alpha(2A), alpha(2C), H-1, M-1, M-3, and M-5 receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT1A agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.
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