AZD3676

AZD3676 is an orally active and blood-brain barrier-permeable ligand for 5-HT_1A and 5-HT_1B receptors, with nanomolar binding affinity for human and monkey receptors (human 5-HT_1A: 0.16 nM, monkey 5-HT_1A: 0.13 nM, human 5-HT_1B: 2.3 nM, monkey 5-HT_1B: 2.4 nM). AZD3676 is applicable to research related to cognitive impairment in Alzheimer's disease^[1]. In Vitro:AZD3676 (1 pM-100 nM (5-HT_1A); 0.01 nM-1 μM (5-HT_1B); 16 h, room temperature) exhibits nanomolar affinity for 5-HT_1A (K_i = 0.13 nM) and 5-HT_1B (K_i = 2.4 nM) receptors in cynomolgus monkey brain homogenates^[1].
AZD3676 (0.4-20 μM; ~1 μM (predicted C_max)) shows concentration-dependent plasma protein binding, with species-specific unbound fractions ranging from 0.014 (human) to 0.37 (guinea pig) at the predicted therapeutic maximum concentration of ~1 μM^[1]. In Vivo:AZD3676 (10 μmol/kg; s.c.; single dose) significantly reverses R-8-OH-DPAT-induced cognitive impairment in C57BL/6 mice, as demonstrated by restored freezing behavior in a contextual fear conditioning assay^[1].
AZD3676 (1-10 μmol/kg; s.c., p.o.; single dose) significantly reverses Scopolamine(HY-N0296)-induced cognitive impairment in C57BL/6 mice, as demonstrated by restored freezing behavior in a contextual fear conditioning assay^[1].
AZD3676 (0.03-3 μmol/kg; s.c.; single dose) dose-dependently occupies 5-HT₁ₐ receptors in healthy C57BL/6 mice, with a half-maximum receptor occupancy of 0.05 μmol/kg s.c. in the frontal cortex^[1].
AZD3676 (0.1-10 μmol/kg; s.c.; single dose) dose-dependently occupies 5-HT_1A receptors in healthy Sprague Dawley rats, with a half-maximum receptor occupancy of 0.17 μmol/kg s.c. in the frontal cortex^[1].
AZD3676 (0.3-10 μmol/kg; s.c.; single dose) dose-dependently occupies 5-HT₁A and 5-HT₁B receptors in healthy Dunkin Hartley guinea pigs, with half-maximum receptor occupancy values of 0.3 μmol/kg s.c. and 1.2 μmol/kg s.c., respectively^[1].
AZD3676 (0.16-0.82 μmol/kg; i.v.; maintenance infusion following initial low-dose bolus) dose-dependently occupies 5-HT_1A receptors in healthy cynomolgus monkeys, with a K_i,plasma of 84 nM for half-maximum occupancy in the prefrontal cortex^[1].
AZD3676 (0.1-1.8 μmol/kg; i.v.; maintenance infusion following initial low-dose bolus) dose-dependently occupies 5-HT₁B receptors in healthy cynomolgus monkeys, with a K_i,plasma of 72 nM for half-maximum occupancy in the occipital cortex^[1].