2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242) is a novel κ-opioid receptor (KOR) antagonist with high affinity for human (3 nM), rat (21 nM), and mouse (22 nM) KOR, a ∼ 20-fold reduced affinity for human μ-opioid receptors (MORs; K(i) = 64 nM), and negligible affinity for δ-opioid receptors (K(i) > 4 μM). PF-04455242 also showed selectivity for KORs in vivo. In rats, PF-04455242 blocked KOR and MOR agonist-induced analgesia with ID(50) values of 1.5 and 9.8 mg/kg, respectively, and inhibited ex vivo [(3)H](2-(benzofuran-4-yl)-N-methyl-N-((5S,7R,8R)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]decan-8-yl)acetamide ([(3)H]CI977) and [(3)H](2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl) propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3-phenylpropanamide ([(3)H]DAMGO) binding to KOR and MOR receptors with ID(50) values of 2.0 and 8.6 mg/kg, respectively. An in vivo binding assay was developed using (-)-4-[(3)H]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(3)H]PF-04767135), a tritiated version of the KOR positron emission tomography ligand (-)-4-[(11)C]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(11)C]GR103545) in which PF-04455242 had an ID(50) of 5.2 mg/kg. PF-04455242 demonstrated antidepressant-like efficacy (mouse forced-swim test), attenuated the behavioral effects of stress (mouse social defeat stress assay), and showed therapeutic potential in treating reinstatement of extinguished cocaine-seeking behavior (mouse conditioned place preference). KOR agonist-induced plasma prolactin was investigated as a translatable mechanism biomarker. Spiradoline (0.32 mg/kg) significantly increased rat plasma prolactin levels from 1.9 ± 0.4 to 41.9 ± 4.9 ng/ml. PF-04455242 dose-dependently reduced the elevation of spiradoline-induced plasma prolactin with an ID(50) of 2.3 ± 0.1 mg/kg, which aligned well with the ED(50) values obtained from the rat in vivo binding and efficacy assays. These data provide further evidence that KOR antagonists have potential for the treatment of depression and addiction disorders.

中文翻译：

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2-甲基-N-（（2'-（吡咯烷基-1-基磺酰基）联苯-4-基）甲基）丙-1-胺（PF-04455242）的药理特性受体。

2-甲基-N-（（（2'-（吡咯烷-1-基磺酰基）联苯-4-基）甲基）丙-1-胺（PF-04455242）是一种新型的具有高亲和力的κ阿片受体（KOR）拮抗剂对于人（3 nM），大鼠（21 nM）和小鼠（22 nM）KOR，与人μ阿片受体（MOR; K（i）= 64 nM）的亲和力降低约20倍，而对人的阿片受体的亲和力可忽略不计δ阿片受体（K（i）> 4μM）。PF-04455242还显示了体内KOR的选择性。在大鼠中，PF-04455242以ID（50）值分别为1.5和9.8 mg / kg阻断了KOR和MOR激动剂引起的镇痛作用，并抑制了离体[（3）H]（2-（苯并呋喃-4-基） -N-甲基-N-（（（5S，7R，8R）-7-（吡咯烷-1-基）-1-氧天青] [4。5] decan-8-基）乙酰胺（[[（3）H] Cl977）和[（3）H]（2S）-2-[[2-[[（2R）-2-[[（2S）-2 -氨基-3-（4-羟基苯基）丙酰基]氨基]丙酰基]氨基]乙酰基]-甲基氨基] -N-（2-羟基乙基）-3-苯基丙酰胺（[[3）H] DAMGO）与KOR和MOR受体结合ID（50）值分别为2.0和8.6 mg / kg。使用（-）-4-[（3）H]甲氧羰基-2-[[（1-吡咯烷基甲基）-1-[（3,4-二氯苯基）乙酰基]-哌啶（[（3） H] PF-04767135），KOR正电子发射断层成像配体（-）-4-[（11）C]甲氧基羰基-2-[（1-吡咯烷基甲基）-1-[（3,4-二氯苯基）]的a版PF-04455242的ID（50）为5.2 mg / kg的乙酰基]-哌啶（[（11）C] GR103545）。PF-04455242表现出抗抑郁样功效（小鼠强迫游泳试验），减弱了其行为影响压力（鼠标社交失败压力分析），并显示了在恢复已熄灭的可卡因寻求行为（小鼠有条件的位置偏爱）方面的治疗潜力。研究了KOR激动剂诱导的血浆催乳素作为可翻译的机制生物标志物。螺旋体（0.32 mg / kg）可将大鼠血浆催乳素水平从1.9±0.4 ng / ml显着增加至41.9±4.9 ng / ml。PF-04455242剂量依赖性地降低了spiradoline诱导的血浆催乳激素的升高，其ID（50）为2.3±0.1 mg / kg，与从大鼠体内结合和功效试验获得的ED（50）值非常吻合。这些数据提供了进一步的证据，表明KOR拮抗剂具有治疗抑郁症和成瘾症的潜力。研究了KOR激动剂诱导的血浆催乳素作为可翻译的机制生物标志物。螺旋体（0.32 mg / kg）可将大鼠血浆催乳素水平从1.9±0.4 ng / ml显着增加至41.9±4.9 ng / ml。PF-04455242剂量依赖性地降低了spiradoline诱导的血浆催乳激素的升高，其ID（50）为2.3±0.1 mg / kg，与从大鼠体内结合和功效试验获得的ED（50）值非常吻合。这些数据提供了进一步的证据，表明KOR拮抗剂具有治疗抑郁症和成瘾症的潜力。研究了KOR激动剂诱导的血浆催乳素作为可翻译的机制生物标志物。螺旋体（0.32 mg / kg）可将大鼠血浆催乳素水平从1.9±0.4 ng / ml显着增加至41.9±4.9 ng / ml。PF-04455242剂量依赖性地降低了spiradoline诱导的血浆催乳激素的升高，其ID（50）为2.3±0.1 mg / kg，与从大鼠体内结合和功效测定获得的ED（50）值很好地吻合。这些数据提供了进一步的证据，表明KOR拮抗剂具有治疗抑郁症和成瘾症的潜力。它与从大鼠体内结合和功效测定中获得的ED（50）值非常吻合。这些数据提供了进一步的证据，表明KOR拮抗剂具有治疗抑郁症和成瘾症的潜力。它与从大鼠体内结合和功效测定中获得的ED（50）值非常吻合。这些数据提供了进一步的证据，表明KOR拮抗剂具有治疗抑郁症和成瘾症的潜力。