N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity.
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-HT(1A), 5-HT(1E), 5-HT(2A), 5-HT(2B), 5-HT(7) 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-HT(1D), 5-HT(2C), 5-HT(3), 5-HT(5), 5-HT(6), 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-HT(1A) receptor. N-Desalkylquetiapine was an antagonist at 5-HT(2A), 5-HT(2B), 5-HT(2C), 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-HT(1A) agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.
Department of Pharmacology, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.
Niels H
NH
Jensen
Ramona M
RM
Rodriguiz
Marc G
MG
Caron
William C
WC
Wetsel
Richard B
RB
Rothman
Bryan L
BL
Roth
D018759:Adrenergic Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003987:Dibenzothiazepines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000069348:Quetiapine Fumarate; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D000069348:Quetiapine Fumarate