Norquetiapine

Norquetiapine ( N-Desalkylauetiapine), a metabolite of Quetiapine (HY-14544), is a selective HCN1 channel inhibitor, with an IC₅₀ of 13.9 μM. Norquetiapine selectively inhibits noradrenaline reuptake, is a partial 5-HT_1A (K_i = 45 nM) receptor agonist, and acts as an antagonist at presynapticα2 (K_i = 237 nM), 5-HT_2C(K_i = 107 nM), and 5-HT₇ (K_i = 76 nM) receptors. Norquetiapine blocks the human cardiac sodium channel Nav1.5 in a state-dependent manner. Norquetiapine shows partial anti-inflammatory effects in LPS (HY-D1056) injected C57BL/6 mice. Norquetiapine can be used for the study of depression and inflammation^{[1][2][3][4][5]}. In Vitro:Norquetiapine (5 μM) blocks the human cardiac sodium channel Nav1.5 in a state-dependent manner ^[1].
Norquetiapine (10-30 μM, 7.5-30 min) selectively inhibits HCN1 currents in Xenopus laevis oocytes by shifting the voltage-dependence of activation to more hyperpolarized potentials and slowing channel opening, with an IC₅₀ of 13.9 μM^[2].
Norquetiapine (30 μM, 7.5-15 min) inhibits HCN4 channels in Xenopus laevis oocytes with reduced efficacy compared to HCN1 and has no significant effect on HCN2 channels^[2].
Norquetiapine (30 μM, 7.5 min) inhibits HCN1 channels primarily from the closed state in Xenopus laevis oocytes, with minimal effect on open-state channels^[2].
Norquetiapine exhibits varying affinities for multiple receptors and the norepinephrine transporter (NET) with K_i values as follows: 196 nM for D₂, 48 nM for 5-HT_2A, 107 nM for 5-HT_2C, 45 nM for 5-HT_1A, 76 nM for 5-HT₇, 3.5 nM for H₁, 144 nM for Alpha-1, 237 nM for Alpha-2, and 58 nM for NET^[4].
In Vivo:Norquetiapine (10 mg/kg, i.p., once daily, 14 days) shows partial anti-inflammatory effects on IL-10 and IFN-γ in serum and brain following acute LPS challenge in male C57BL/6 mice^[3].
Norquetiapine (0.1-1.0 mg/kg, i.p., daily, 12-14 days) displays potent antidepressant-like activity in VMAT2 heterozygous mice^[5].