McQuade R D, Chipkin R, Amlaiky N, Caron M, Iorio L, Barnett A
Research Division, Schering-Plough Corp., Bloomfield, NJ 07003.
Life Sci. 1988;43(14):1151-60. doi: 10.1016/0024-3205(88)90474-2.
A new radioiodinated molecule, 125I-SCH 38840 (previously referred to as 125I-SCH 23982), has been recently reported to be a D-1 dopamine receptor ligand. The current study confirms and expands the characterization of both the radiolabeled and unlabeled forms of this compound, as well as describing the development of an in vivo D-1 receptor binding assay utilizing the 125I-SCH 38840. The binding of 125I-SCH 38840 to rat striatal membranes, in vitro, was saturable and exhibited a KD of 1.47 nM. Competition studies using 125I-SCH 38840 exhibited a pharmacological profile consistent with the proposal that 125I-SCH 38840 was binding to the D-1 receptor. Further studies with the unlabeled SCH 38840 demonstrated that it inhibited dopamine-stimulated adenylate cyclase with a KI of 66.1 nM, indicating that SCH 38840 was acting as a D-1 antagonist. Behavioral studies demonstrated that SCH 38840 (MED = 1.0 mg/kg, s.c.) blocked conditioned avoidance responding in rats, a measurement considered predictive of anti-psychotic activity in man. In vivo binding of 125I-SCH 38840 to rat striatum following s.c. administration was specific. Peak striatal levels were observed 1 h after injection, with measurable binding observed out to 8 h post-treatment. The displacement of the in vivo binding by unlabeled standards again suggested a D-1 selective interaction. The half-life of the in vivo binding of 125I-SCH 38840 was approximately 1.25 h, and was nearly equivalent to the half-life of the anti-CAR activity of unlabeled SCH 38840. These results clearly demonstrate the D-1 nature of SCH 38840's behavioral activity and strengthen the anti-psychotic potential of a D-1 antagonist.
最近有报道称，一种新的放射性碘化分子125I-SCH 38840（以前称为125I-SCH 23982）是一种D-1多巴胺受体配体。本研究证实并扩展了该化合物放射性标记形式和未标记形式的特性描述，同时还描述了利用125I-SCH 38840进行体内D-1受体结合测定的方法。体外实验中，125I-SCH 38840与大鼠纹状体膜的结合具有饱和性，解离常数（KD）为1.47 nM。使用125I-SCH 38840进行的竞争研究显示出的药理学特征与125I-SCH 38840与D-1受体结合的提议一致。对未标记的SCH 38840的进一步研究表明，它抑制多巴胺刺激的腺苷酸环化酶，抑制常数（KI）为66.1 nM，表明SCH 38840作为D-1拮抗剂发挥作用。行为学研究表明，SCH 38840（肌肉注射半数有效剂量=1.0 mg/kg）可阻断大鼠的条件性回避反应，这一指标被认为可预测人类的抗精神病活性。皮下注射后，125I-SCH 38840在大鼠纹状体中的体内结合具有特异性。注射后1小时观察到纹状体中的峰值水平，治疗后8小时仍可观察到可测量的结合。未标记标准品对体内结合的置换再次表明存在D-1选择性相互作用。125I-SCH 38840体内结合的半衰期约为1.25小时，几乎与未标记的SCH 38840的抗CAR活性半衰期相当。这些结果清楚地证明了SCH 38840行为活性的D-1性质，并增强了D-1拮抗剂的抗精神病潜力。
