Beyer C E, Lin Q, Platt B, Malberg J, Hornby G, Sullivan K M, Smith D L, Lock T, Mitchell P J, Hatzenbuhler N T, Evrard D A, Harrison B L, Magolda R, Pangalos M N, Schechter L E, Rosenzweig-Lipson S, Andree T H
Discovery Neuroscience, Wyeth Research, Princeton, NJ 08543-8000, USA.
Br J Pharmacol. 2009 May;157(2):307-19. doi: 10.1111/j.1476-5381.2009.00146.x. Epub 2009 Mar 26.
As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT(1A) receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT(1A) receptor antagonist activities, was evaluated in preclinical models.
Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.
WAY-211612 inhibited 5-HT reuptake (K(i) = 1.5 nmol.L(-1); K(B) = 17.7 nmol.L(-1)) and exhibited full 5-HT(1A) receptor antagonist activity (K(i) = 1.2 nmol.L(-1); K(B) = 6.3 nmol.L(-1); I(max) 100% in adenyl cyclase assays; K(B) = 19.8 nmol.L(-1); I(max) 100% in GTPgammaS). WAY-211612 (3 and 30 mg.kg(-1), po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT(1A) receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3-30 mg.kg(-1), po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg.kg(-1), s.c.) and a 5-HT(1A) antagonist (WAY-100635; 0.3 mg.kg(-1), s.c). WAY-211612 (3.3-30 mg.kg(-1), s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3-30 mg.kg(-1), i.p. and 10-56 mg.kg(-1), po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg.kg(-1), i.p.) in the rat scheduled-induced polydipsia model.
These findings suggest that WAY-211612 may represent a novel antidepressant.
5-羟色胺（5-HT）选择性再摄取抑制剂（SSRI）与5-HT（1A）受体拮抗剂联合使用可能会产生速效抗抑郁药，因此对兼具SSRI和5-HT（1A）受体拮抗剂活性的化合物WAY-211612进行了临床前模型评估。
占有率研究证实了WAY-211612的作用机制，同时在微透析和行为模型中对其体内特征进行了表征。
WAY-211612抑制5-HT再摄取（K(i)=1.5 nmol.L(-1)；K(B)=17.7 nmol.L(-1)），并表现出完全的5-HT(1A)受体拮抗剂活性（K(i)=1.2 nmol.L(-1)；K(B)=6.3 nmol.L(-1)；在腺苷酸环化酶测定中I(max)为100%；K(B)=19.8 nmol.L(-1)；在GTPγS中I(max)为100%）。WAY-211612（3和30 mg.kg(-1)，口服）占据大鼠前额叶皮质（分别为56.6%和73.6%）和海马体（52.2%和78.5%）中的5-HT再摄取位点，以及前额叶皮质（6.7%和44.7%）、海马体（8.3%和48.6%）和中缝背核（15%和83%）中的5-HT(1A)受体。WAY-211612（3 - 30 mg.kg(-1)，口服）急性或慢性治疗可使皮质5-HT水平提高约两倍，SSRI（氟西汀；30 mg.kg(-1)，皮下注射）和5-HT(1A)拮抗剂（WAY-100635；0.3 mg.kg(-1)，皮下注射）联合使用时也观察到这种情况。WAY-211612（3.3 - 30 mg.kg(-1)，皮下注射）可减少定居者-入侵者模型中的攻击行为，同时增加小鼠四板模型中受罚穿越的次数（3 - 30 mg.kg(-1)，腹腔注射和10 - 56 mg.kg(-1)，口服），并减少大鼠定时诱导多饮模型中的辅助饮水行为（56 mg.kg(-1)，腹腔注射）。
这些发现表明WAY-211612可能是一种新型抗抑郁药。
