Studies of Biogenic Amine Transporter Inhibitors

生物胺转运蛋白抑制剂的研究

• 批准号: 7733850
• 负责人: Richard Rothman
• 金额: $ 19.92万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733850
• 关键词: Acids; Affect; Affinity; Amphetamines; Back; Binding; Biogenic Amines; Biological Assay; Brain; Carrier Proteins; Cell membrane; Cells; Chromosome Pairing; Class; Cytoplasm; Development; Dissociation; Dopamine; Dose; Drug Delivery Systems; Esters; Evaluation; Extracellular Space; Human Cloning; Hydroxyl Radical; Knowledge; Laboratories; Mediating; Membrane; Membrane Proteins; Mental disorders; Methods; Modeling; Nerve; Neuraxis; Neurons; Neurotransmitters; Norepinephrine; Pharmaceutical Preparations; Pharmacotherapy; Piperazines; Procedures; Process; Psychostimulant dependence; Publishing; Range; Rate; Rattus; Reporting; Role; Serotonin; Sigmoid colon; Signal Transduction; Site; Structure; Synapses; Synaptosomes; Therapeutic; Vesicle; analog; base; carbene; design; dopamine transporter; dopaminergic neuron; drug of abuse; extracellular; inhibitor/antagonist; monoamine; noradrenaline transporter; novel; piperazine; piperidine; protein function; psychostimulant; research study; response; reuptake; serotonin transporter; uptake

Significant progress was made on this project during this reporting period. Several structure-activity studies were reported. One examined the DAT/SERT selectivity of flexible GBR12909 analogs modeled using 3D-QSAR methods. A second reported the design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-2-bis(4-fluorophenyl)methoxyethyl-4-(3-phenylpropyl)piperazine and 1-2-(diphenylmethoxy)ethyl-4-(3-phenylpropyl)piperazine: role of amino, fluoro, hydroxyl, methoxyl, methyl, methylene, and oxo substituents on affinity for the dopamine and serotonin transporters. We also made progress in identifying novel partial inhibitors of amphetamine-induced dopamine release. In particular, we reported: "Previous studies identified partial inhibitors and allosteric modulators of 5-HT (5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido3,4-bpyrazin-7-ylcarbamic acid ethyl ester SoRI-6238, 4-(2-bis(4-fluorophenyl)methoxyethyl)-1-(2-trifluoromethyl-benzyl)-piperidine TB-1-099) and dopamine transporters N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine, SoRI-9804). We report here the identification of three novel allosteric modulators of the dopamine transporter N-(2,2-Diphenylethyl)-2-phenyl-4-quinazolinamine SoRI-20040, N-(3,3-Diphenylpropyl)-2-phenyl-4-quinazolinamine SoRI-20041, 4-Amino-6-(diphenylmethyl)amino-5-nitro-2-pyridinylcarbamic acid ethyl ester, SoRI-2827). Membranes were prepared from HEK cells expressing the cloned human dopamine (hDAT) transporter. 125IRTI-55 binding and other assays followed published procedures. SoRI-20040, SoRI-20041 and SoRI-2827 partially inhibited 125IRTI-55 binding with EC50 values ranging from 1.4 M to 3 M and EMAX values decreasing as the 125IRTI-55 concentrations increased. All three compounds decreased the 125IRTI-55 Bmax and increased the apparent Kd in a manner well described by a sigmoid dose-response curve. In dissociation rate experiments, SoRI-20040 (10 M) and SoRI-20041 (10 M), but not SoRI-2827 (10 M), slowed the dissociation of 125IRTI-55 from hDAT by 30%. Using rat brain synaptosomes, all three agents partially inhibited 3Hdopamine uptake with EC50 values ranging from 1.8 M to 3.1 M and decreased the VMAX value in a dose-dependent manner. SoRI-9804 and SoRI-20040 partially inhibited amphetamine-induced DAT-mediated release of 3HMPP+ from rat caudate synaptosomes in a dose-dependent manner. Viewed collectively, we report several compounds that allosterically modulate hDAT binding and function, and identify novel partial inhibitors of amphetamine-induced dopamine release."

在此报告期间，该项目取得了重大进展。报道了几项结构性研究。一个人检查了使用3D-QSAR方法建模的灵活GBR12909类似物的DAT/SERT选择性。第二个报道了1-2-双（4-氟苯基）甲氧乙基-4-（3-苯基丙基）丙吡啶和1-2-的2-和3-基因3-苯基丙基类似物的设计和合成。对多巴胺和5-羟色胺转运蛋白的亲和力，甲氧基，甲基，甲基和氧取代基。我们还取得了鉴定苯丙胺诱导的多巴胺释放的新型部分抑制剂的进展。我们特别报告： “先前的研究确定了5-HT（5-Amino-3-（3,4-二氯苯基）-1,1,2-二氢吡啶的部分抑制剂和变构调节剂， 4-（2-双（4-氟）甲氧乙基）-1-（2-三氟甲基 - 苯基）-Piperidine-piperidine TB-1-099）和多巴胺转运蛋白N-（二苯基苯基甲基） - 2-苯基甲基）-2-苯基 - 4-苯基 - 4- Quinazolinamine notialsion sorers sori-98804。多巴胺转运蛋白N-（2,2-二苯基乙基）-2-苯基-4-喹唑啉胺Sori-20040，N-（3,3-二苯基丙基）-2-苯基-4-苯基-4quinazolinamine氨基胺-20041乙酯，Sori-2827）。 125 tirti-55浓度增加。所有三种化合物都降低了125 tirti-55 Bmax，并以sigmoid剂量反应曲线很好地描述的方式增加了明显的KD。在分离率实验中，SORI-20040（10 M）和Sori-20041（10 M），但不是Sori-2827（10 m），使HDAT的125 tirti-55速度减慢了30％。使用大鼠脑突触体，所有三种药物部分抑制了3hdopamine的摄取，EC50值范围为1.8 m至3.1 m，并以剂量​​依赖性方式降低了VMAX值。 SORI-9804和SORI-20040部分抑制了苯丙胺诱导的DAT介导的3HMPP释放，以剂量依赖性方式从大鼠尾状突触体中释放。总体观察，我们报告了几种化合物，它们可以调节HDAT结合和功能，并确定苯丙胺诱导的多巴胺释放的新型部分抑制剂。”