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New Dopamine D2 Receptor Agonist, [3H]MCL-536, for Detecting Dopamine D2high Receptors in Vivo
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-04-11 00:00:00 , DOI: 10.1021/acschemneuro.8b00096
Sivan Subburaju 1, 2 , Anna W Sromek 1, 2 , Philip Seeman 3 , John L Neumeyer 1, 2
Affiliation  

Increases in the D2 receptor high affinity state are associated with certain neurological disorders. We synthesized and characterized the high-affinity D2high ligand [3H]MCL-536 in competition binding against the D2/3 agonist R-(−)-N-n-propylnorapomorphine (NPA) and the D2/3 antagonist raclopride. The total binding of [3H]MCL-536 (minus that in the presence of 100 nM NPA) was measured by saturation binding in CHO cells expressing human D2long; the data yielded separable, nonsaturable nonspecific, and saturable specific components. The former represents an aporphine site common to NPA and [3H]MCL-536. The latter indicated specific binding to the total D2 receptors (both high and low-affinity states). [3H]MCL-536 had a Kd of 0.8 nM. In competition binding, NPA had a Ki of 0.16 nM, and raclopride had a Ki of 0.9 nM. Co-incubation with guanylylimidodiphosphate abolished binding to D2high. This unique profile makes radiolabeled MCL-536 a versatile tool for diagnostics and therapeutics, and may quantify D2high sites in schizophrenia and PD patients in vivo.

中文翻译:

新型多巴胺 D2 受体激动剂 [3H]MCL-536,用于检测体内多巴胺 D2 高受体

D2 受体高亲和力状态的增加与某些神经系统疾病有关。我们合成并表征了高亲和力 D2high 配体 [ 3 H] MCL-536 与 D2/3 激动剂R -(-)- N - n -丙基去甲吗啡 (NPA) 和 D2/3 拮抗剂 raclopride 的竞争结合。[ 3 H]MCL-536的总结合(减去在100 nM NPA存在下的结合)通过在表达人D2long的CHO细胞中的饱和结合来测量;数据产生了可分离的、不可饱和的非特异性和可饱和的特异性成分。前者代表 NPA 和 [ 3H]MCL-536。后者表明与总 D2 受体(高亲和力和低亲和力状态)的特异性结合。[ 3 H]MCL-536 的K d为 0.8 nM。在竞争结合中,NPA 的K i为 0.16 nM,raclopride 的K i为 0.9 nM。与鸟苷酰亚氨基二磷酸共同孵育消除了与 D2high 的结合。这种独特的特征使放射性标记的 MCL-536 成为诊断和治疗的多功能工具,并可在体内量化精神分裂症和 PD 患者的 D2high 位点。
更新日期:2018-04-11
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