WAY-100635 is a highly potent and selective 5-hydroxytryptamine 1A (5-HT1A) receptor antagonist with an IC50 value of 0.91nM and a Ki value of 0.39nM[1,2]. The 5-HT1A receptor is widely distributed in the central nervous system (e.g., hippocampus, amygdala) and peripheral nervous tissues (e.g., enteric nerves and cardiovascular system), playing a crucial role in regulating emotional states and the secretion of various hormones[3]. WAY-100635 is also a potent full agonist of the dopamine D4 receptor and is commonly used in positron emission tomography (PET) imaging, neuroscience, and behavioral and cognitive studies[4].
In vitro, pretreatment of human neuroblastoma SH-SY5Y cells with WAY-100635 (10μM) for 1h significantly inhibited the increase in cell viability induced by co-treatment with the antidepressant fluoxetine (1μM) and Aβo (5μM) for 24h[5]. In rat hippocampal homogenates, incubation with WAY-100635 (0.2μM) together with the 5-HT1A receptor agonist (+)-5-Me-8-OH-DPAT for 20min completely blocked the inhibition of forskolin-stimulated cAMP production induced by (+)-5-Me-8-OH-DPAT[6].
In vivo, subcutaneous injection of WAY-100635 (0.1mg/kg) in Albino Swiss mice 15min before treatment completely blocked the hypothermic effect induced by the 5-HT1A receptor agonist 8-OH-DPAT (5mg/kg)[7]. Intraperitoneal injection of WAY-100635 (0.1, 0.2, 0.4mg/kg) in chronic constriction injury (CCI) model mice receiving chrysin treatment dose-dependently reversed the alleviating effects of chrysin on heat hyperalgesia and mechanical allodynia[8].
References:
[1] FORNAL C A, METZLER C W, GALLEGOS R A, et al. WAY-100635, a potent and selective 5-hydroxytryptamine1A antagonist, increases serotonergic neuronal activity in behaving cats: comparison with (S)-WAY-100135[J]. The Journal of pharmacology and experimental therapeutics, 1996, 278(2): 752-762.
[2] AL HUSSAINY R, VERBEEK J, VAN DER BORN D, et al. Design, synthesis, radiolabeling, and in vitro and in vivo evaluation of bridgehead iodinated analogues of N-{2-[4-(2-methoxyphenyl) piperazin-1-yl] ethyl}-N-(pyridin-2-yl) cyclohexanecarboxamide (WAY-100635) as potential SPECT ligands for the 5-HT1A receptor[J]. Journal of medicinal chemistry, 2011, 54(10): 3480-3491.
[3] SAVITZ J, LUCKI I, DREVETS W C. 5-HT1A receptor function in major depressive disorder[J]. Progress in neurobiology, 2009, 88(1): 17-31.
[4] CLIFFE I A. A retrospect on the discovery of WAY-100635 and the prospect for improved 5-HT1A receptor PET radioligands[J]. Nuclear medicine and biology, 2000, 27(5): 441-447.
[5] YAMAMOTO K, TSUJI M, OGUCHI T, et al. Comparison of Protective Effects of Antidepressants Mediated by Serotonin Receptor in Aβ-Oligomer-Induced Neurotoxicity[J]. Biomedicines, 2024, 12(6): 1158.
[6] TRILLAT A C, MALAGIÉ I, MATHÉ-ALLAINMAT M, et al. Effects of WAY 100635 and (-)-5-Me-8-OH-DPAT, a novel 5-HT1A receptor antagonist, on 8-OH-DPAT responses[J]. European journal of pharmacology, 1998, 347(1): 41-49.
[7] WESOLOWSKA A, BORYCZ J, PALUCHOWSKA M H, et al. Pharmacological analysis of the hypothermic effects of NAN-190 and its analogs, postsynaptic 5-HT1A receptor antagonists, in mice[J]. Polish journal of pharmacology, 2002, 54(4): 391-399.
[8] WU J, WANG Y, CUI W, et al. 5-HT1A receptor-mediated attenuation of heat hyperalgesia and mechanical allodynia by chrysin in mice with experimental mononeuropathy[J]. Regional Anesthesia & Pain Medicine, 2020, 45(8): 610-619.
WAY-100635是一种具有高效性选择的5-hydroxytryptamine 1A（5-HT1A）受体拮抗剂，IC50值为0.91nM，Ki值为0.39nM[1,2]。5-HT1A广泛分布于中枢神经系统（如海马体、杏仁核）和外周神经组织（肠道神经及心血管系统）中，对调节情绪状态及多种激素的分泌均至关重要[3]。WAY-100635也是多巴胺D4受体的强效完全激动剂，通常用于正电子发射断层（PET）成像、神经科学及行为与认知研究[4]。
在体外，WAY-100635（10μM）预处理人类神经母细胞瘤SH-SY5Y细胞1h，显著抑制了由抗抑郁药fluoxetine（1μM）联合Aβo（5μM）处理24h所引起的细胞活力增加[5]。WAY-100635（0.2μM）处理大鼠海马组织匀浆，与5-HT1A受体激动剂(+)-5-Me-8-OH-DPAT共孵育20min，完全阻断了(+)-5-Me-8-OH-DPAT诱导的Forskolin刺激的cAMP生成抑制[6]。
在体内，WAY-100635（0.1mg/kg）通过皮下注射处理Albino Swiss小鼠15min，完全阻断了5-HT1A受体激动剂8-OH-DPAT（5mg/kg）诱导的低体温效应[7]。WAY-100635（0.1, 0.2, 0.4mg/kg）通过腹腔注射处理接受Chrysin治疗的慢性压迫损伤（CCI）模型小鼠，剂量依赖性地逆转了Chrysin对热痛觉过敏和机械性异常性疼痛的缓解作用[8]。