SYNTHESIS AND EVALUATION OF CNS, ANTIINFLAMMATORY, AND ANTICANCER AGENTS

中枢神经系统、抗炎和抗癌药物的合成和评价

• 批准号: 4689164
• 负责人: K C RICE
• 金额: --
• 依托单位: NAT INST OF ARTHRITIS, DIABETES, DIGESTIVE & KIDNEY DISEASES
• 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/4689164
• 关键词: antiinflammatory agents; centrally acting drug; chemical binding; chemical structure function; chlorpromazine; codeine; conformation; dopamine; drug design /synthesis /production; drug metabolism; drug screening /evaluation; methylphenidate; molecular site; muscle stimulant; neuropharmacology; phencyclidine; phenothiazines; psychotropic drugs; stereoisomer; synaptosomes

Saturable and stereospecific binding sites for tritium labeled threo-(plus or minus)-methylphenidate were characterized in rat brain membranes. The highest density of labeled threo-(plus or minus)-methylphenidate binding sites was found in the synaptosomal fraction of corpus striatum. Scatchard analysis revealed a single class of non-interacting binding sites with an apparent dissociation constant (Kd) of 235 nM and a maximum number of binding sites (Bmax) of 13.4 pmol/mg protein. Saturable, high affinity binding of labeled threo-(plus or minus)-methylphenidate to striatal synaptosomes was dependent upon the presence of sodium ions. A good correlation (r = 0.88; p less than 0.001) was observed between the potencies of various psychotropic drugs in displacing labeled threo-(plus or minus)-methylphenidate from these sites and their potencies as inhibitors of (H3)dopamine uptake into striatal synaptosomes. A good correlation (r = 0.85; p less than 0.001) was also observed between the potencies of a series of ritalinic acid esters in inhibiting labeled threo(plus or minus)-methylphenidate binding to striatal synaptosomes and their potencies as motor stimulants in mice. These observations suggest that the binding sites for labeled threo-(plus or minus)-methylphenidate described here are associated with a dopamine uptake or transport complex, and that these sites may mediate the motor stimulant properties of ritalinic acid esters such as methylphenidate.

氚标记的苏-（加上 或负）-哌甲酯在大鼠脑膜中进行了表征。 这 标记苏型（正或负）哌甲酯结合的最高密度 在纹状体的突触体部分中发现了这些位点。 斯卡查德 分析揭示了一类非相互作用的结合位点 表观解离常数 (Kd) 为 235 nM，最大数量 13.4 pmol/mg 蛋白质的结合位点 (Bmax)。 饱和、高亲和力 标记的苏型（正或负）哌甲酯与纹状体的结合 突触体依赖于钠离子的存在。 一个好的 观察到相关性（r = 0.88；p 小于 0.001） 各种精神药物在取代标记的苏-（加上 或减）-哌甲酯来自这些位点及其效力 (H3)多巴胺摄取纹状体突触体的抑制剂。 一个好的 还观察到相关性（r = 0.85；p 小于 0.001） 一系列哌醋甲酯抑制标记物的效力 苏型（正或负）-哌醋甲酯与纹状体突触体结合和 它们作为小鼠运动兴奋剂的效力。 这些观察表明 标记的苏型（正或负）哌甲酯的结合位点 这里描述的与多巴胺摄取或运输复合物有关， 这些位点可能介导运动兴奋特性 哌醋甲酯等哌醋甲酯。