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F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. I. In vitro receptor affinity and efficacy profile.F15063，一种具有D2/D3拮抗剂、5-羟色胺1A激动剂和D4部分激动剂特性的潜在抗精神病药物。I. 体外受体亲和力和效能概况。
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F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. II. Activity in models of positive symptoms of schizophrenia.F15063，一种具有D2/D3拮抗剂、5-羟色胺1A激动剂和D4部分激动剂特性的化合物。二、在精神分裂症阳性症状模型中的活性。
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Br J Pharmacol. 2007 May;151(2):253-65. doi: 10.1038/sj.bjp.0707159. Epub 2007 Mar 20.

本文引用的文献

1
Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties.典型、非典型及第三代抗精神病药物在与腺苷酸环化酶偶联的人5-HT7a受体上的差异特征：激动剂和反向激动剂特性的检测
Naunyn Schmiedebergs Arch Pharmacol. 2007 Oct;376(1-2):93-105. doi: 10.1007/s00210-007-0182-6. Epub 2007 Sep 5.
2
F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. II. Activity in models of positive symptoms of schizophrenia.F15063，一种具有D2/D3拮抗剂、5-羟色胺1A激动剂和D4部分激动剂特性的化合物。二、在精神分裂症阳性症状模型中的活性。
Br J Pharmacol. 2007 May;151(2):253-65. doi: 10.1038/sj.bjp.0707159. Epub 2007 Mar 20.
3
F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. III. Activity in models of cognition and negative symptoms.F15063，一种具有D2/D3拮抗剂、5-羟色胺1A激动剂和D4部分激动剂特性的化合物。III. 在认知和阴性症状模型中的活性。
Br J Pharmacol. 2007 May;151(2):266-77. doi: 10.1038/sj.bjp.0707160. Epub 2007 Mar 20.
4
Towards a new generation of potential antipsychotic agents combining D2 and 5-HT1A receptor activities.迈向新一代兼具D2和5-HT1A受体活性的潜在抗精神病药物。
J Med Chem. 2007 Feb 22;50(4):865-76. doi: 10.1021/jm061180b.
5
Native rat hippocampal 5-HT1A receptors show constitutive activity.天然大鼠海马5-羟色胺1A受体表现出组成性活性。
Mol Pharmacol. 2007 Mar;71(3):638-43. doi: 10.1124/mol.106.029769. Epub 2006 Dec 13.
6
The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders.多巴胺D3受体：治疗神经精神疾病的一个治疗靶点。
CNS Neurol Disord Drug Targets. 2006 Feb;5(1):25-43. doi: 10.2174/187152706784111551.
7
Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release.抗精神病药物SSR181507、阿立哌唑和比氟哌隆在多巴胺D2受体上的部分激动剂特性：G蛋白激活和催乳素释放。
Eur J Pharmacol. 2006 Mar 27;535(1-3):135-44. doi: 10.1016/j.ejphar.2006.01.051. Epub 2006 Mar 22.
8
Differential profile of antipsychotics at serotonin 5-HT1A and dopamine D2S receptors coupled to extracellular signal-regulated kinase.抗精神病药物在与细胞外信号调节激酶偶联的5-羟色胺5-HT1A和多巴胺D2S受体上的差异概况
Eur J Pharmacol. 2006 Mar 18;534(1-3):63-70. doi: 10.1016/j.ejphar.2006.01.027. Epub 2006 Feb 21.
9
Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade.新型抗精神病药物对阿扑吗啡诱导的预脉冲抑制破坏的作用：5-羟色胺5-HT1A受体激活与多巴胺D2受体阻断联合的影响
Neuropsychopharmacology. 2006 Sep;31(9):1900-9. doi: 10.1038/sj.npp.1301015. Epub 2006 Jan 18.
10
Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action.前额叶皮质中5-羟色胺1A受体在多巴胺能活性调节中的作用：在非典型抗精神病药物作用中的角色。
J Neurosci. 2005 Nov 23;25(47):10831-43. doi: 10.1523/JNEUROSCI.2999-05.2005.

F15063，一种具有D2/D3拮抗剂、5-羟色胺1A激动剂和D4部分激动剂特性的潜在抗精神病药物。I. 体外受体亲和力和效能概况。

F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. I. In vitro receptor affinity and efficacy profile.

作者信息

Newman-Tancredi A, Assié M-B, Martel J-C, Cosi C, Slot L Bruins, Palmier C, Rauly-Lestienne I, Colpaert F, Vacher B, Cussac D

机构信息

Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France.

出版信息

Br J Pharmacol. 2007 May;151(2):237-52. doi: 10.1038/sj.bjp.0707158. Epub 2007 Mar 20.

DOI:10.1038/sj.bjp.0707158
PMID:17375087
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2013955/
Abstract

BACKGROUND AND PURPOSE

Combining 5-HT(1A) receptor activation with dopamine D(2)/D(3) receptor blockade should improve negative symptoms and cognitive deficits in schizophrenia. We describe the in vitro profile of F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine).

EXPERIMENTAL APPROACH

F15063 was characterised in tests of binding affinity and in cellular models of signal transduction at monoamine receptors.

KEY RESULTS

Affinities (receptor and pK(i) values) of F15063 were: rD(2) 9.38; hD(2L) 9.44; hD(2S) 9.25; hD(3) 8.95; hD(4) 8.81; h5-HT(1A) 8.37. F15063 had little affinity (40-fold lower than D(2)) at other targets. F15063 antagonised dopamine-activated G-protein activation at hD(2), rD(2) and hD(3) receptors with potency (pK (b) values 9.19, 8.29 and 8.74 in [(35)S]GTP gamma S binding experiments) similar to haloperidol. F15063 did not exhibit any hD(2) receptor agonism, even in tests of ERK1/2 phosphorylation and G-protein activation in cells with high receptor expression. In contrast, like (+/-)8-OH-DPAT, F15063 efficaciously activated h5-HT(1A) (E(max) 70%, pEC(50) 7.57) and r5-HT(1A) receptors (52%, 7.95) in tests of [(35)S]GTP gamma S binding, cAMP accumulation (90%, 7.12) and ERK1/2 phosphorylation (93%, 7.13). F15063 acted as a partial agonist for [(35)S]GTP gamma S binding at hD(4) (29%, 8.15) and h5-HT(1D) receptors (35%, 7.68). In [(35)S]GTP gamma S autoradiography, F15063 activated G-proteins in hippocampus, cortex and septum (regions enriched in 5-HT(1A) receptors), but antagonised quinelorane-induced activation of D(2)/D(3) receptors in striatum.

CONCLUSIONS AND IMPLICATIONS

F15063 antagonised dopamine D(2)/D(3) receptors, a property underlying its antipsychotic-like activity, whereas activation of 5-HT(1A) and D(4) receptors mediated its actions in models of negative symptoms and cognitive deficits of schizophrenia (see companion papers).

摘要

背景与目的

将5-羟色胺（5-HT）1A受体激活与多巴胺D2/D3受体阻断相结合，应能改善精神分裂症的阴性症状和认知缺陷。我们描述了F15063（N-[(2,2-二甲基-2,3-二氢-苯并呋喃-7-基氧基)乙基]-3-(环戊-1-烯基)-苄胺）的体外特性。

实验方法

在单胺受体的结合亲和力测试和信号转导细胞模型中对F15063进行了特性鉴定。

主要结果

F15063的亲和力（受体和pK(i)值）为：大鼠D2受体9.38；人D2L受体9.44；人D2S受体9.25；人D3受体8.95；人D4受体8.81；人5-HT1A受体8.37。F15063在其他靶点的亲和力很低（比D2受体低40倍）。在[(35)S]GTPγS结合实验中，F15063拮抗多巴胺激活的人D2、大鼠D2和人D3受体的G蛋白激活，其效力（pK(b)值分别为9.19、8.29和8.74）与氟哌啶醇相似。即使在高受体表达细胞的ERK1/2磷酸化和G蛋白激活测试中，F15063也未表现出任何hD2受体激动作用。相反，与(+/-)8-OH-DPAT一样，在[(35)S]GTPγS结合、cAMP积累（90%，7.12）和ERK1/2磷酸化（93%，7.13）测试中，F15063有效激活人5-HT1A受体（E(max) 70%，pEC(50) 7.57）和大鼠5-HT1A受体（52%，7.95）。F15063在人D4受体（29%，8.15）和人5-HT1D受体（35%，7.68）的[(35)S]GTPγS结合中作为部分激动剂。在[(35)S]GTPγS放射自显影中，F15063激活海马、皮层和隔区（富含5-HT1A受体的区域）的G蛋白，但拮抗喹硫平诱导的纹状体D2/D3受体激活。

结论与意义

F15063拮抗多巴胺D2/D3受体，这是其抗精神病样活性的基础，而5-HT1A和D4受体的激活介导了其在精神分裂症阴性症状和认知缺陷模型中的作用（见配套论文）。