Witkin Jeffrey M, Rorick-Kehn Linda M, Benvenga Mark J, Adams Benjamin L, Gleason Scott D, Knitowski Karen M, Li Xia, Chaney Steven, Falcone Julie F, Smith Janice W, Foss Julie, Lloyd Kirsti, Catlow John T, McKinzie David L, Svensson Kjell A, Barth Vanessa N, Toledo Miguel A, Diaz Nuria, Lafuente Celia, Jiménez Alma, Benito Alfonso, Pedregal Conception, Martínez-Grau Maria A, Post Anke, Ansonoff Michael A, Pintar John E, Statnick Michael A
Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom.
Pharmacol Res Perspect. 2016 Nov 7;4(6):e00275. doi: 10.1002/prp2.275. eCollection 2016 Dec.
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.
孤啡肽/痛敏肽（N/OFQ）是一种由17个氨基酸组成的肽，其受体被命名为ORL1或孤啡肽受体（NOP）。我们使用了一种强效、选择性且口服生物利用度高的拮抗剂，该拮抗剂在体内与NOP受体有明确的结合，以评估NOP受体阻断与抗抑郁和抗焦虑相关的药理作用，以及认知和运动影响的测量。LY2940094（[2-[4-[(2-氯-4,4-二氟-螺[5H-噻吩并[2,3-c]吡喃-7,4'-哌啶]-1'-基)甲基]-3-甲基-吡唑-1-基]-3-吡啶基]甲醇）在小鼠强迫游泳试验中表现出抗抑郁样行为效应，而在NOP基因敲除小鼠中则没有这种效应。LY2940094还增强了氟西汀的行为效应，而不改变靶点占有率（NOP和5-羟色胺再摄取转运体[SERT]）。LY2940094在低速率差别的强化程序下没有作用。虽然在一些动物模型（条件性抑制、四板试验、新奇抑制摄食）中未观察到抗焦虑样效应，但LY2940094在三种试验中具有抗焦虑药物样的作用：小鼠的恐惧条件性僵住、小鼠应激诱导的小脑环磷酸鸟苷增加以及大鼠应激诱导的体温过高。这些是关于系统性可行的NOP受体拮抗剂具有抗焦虑样活性的首次报道。LY2940094在5选串行反应时或延迟位置匹配试验中均未干扰表现。LY2940094也不是啮齿动物运动的激活剂或抑制剂，也未导致转棒试验失败。这些数据表明，LY2940094在啮齿动物中具有独特的与抗抑郁和抗焦虑相关的药理作用。关于该分子在抑郁症患者中的临床概念验证数据已在其他地方报道。
