Campbell A, Baldessarini R J, Kula N S, Ram V J, Neumeyer J L
Brain Res. 1987 Feb 17;403(2):393-7. doi: 10.1016/0006-8993(87)90083-7.
The 10-11-methylenedioxy (MDO) derivative of S(+)N-n-propylnorapomorphine (NPA) was prepared and tested as a possible active prodrug to S(+)NPA, which we have recently found to exert in vivo activity suggestive of selective antagonism of dopamine receptors in the limbic forebrain but not the extrapyramidal basal ganglia. Like S(+)NPA, S(+)MDO-NPA inhibited the behavioral arousal induced by dopamine injected into nucleus accumbens of the rat, but not the head-turning response to dopamine injected into the corpus striatum. However, only MDO-NPA was orally active and it was somewhat longer-acting than NPA. The activity of S(+)MDO-NPA was prevented by pretreatment with the oxidase inhibitor SKF-525A. These properties are analogous to those of R(-)MDO-NPA, which we had previously reported as an orally active prodrug of the dopamine agonist R(-)NPA. Thus the methylenedioxy derivatives of the two entantiomers of NPA have properties desirable in a potentially clinically useful dopamine agonist and limbic dopamine antagonist, respectively.
制备了S(+)N-正丙基去甲阿扑吗啡（NPA）的10-11-亚甲二氧基（MDO）衍生物，并将其作为S(+)NPA的一种可能的活性前药进行测试。我们最近发现S(+)NPA在体内具有活性，提示其对边缘前脑的多巴胺受体具有选择性拮抗作用，而对锥体外系基底神经节则无此作用。与S(+)NPA一样，S(+)MDO-NPA可抑制向大鼠伏隔核注射多巴胺所诱导的行为觉醒，但不能抑制向纹状体注射多巴胺所引起的转头反应。然而，只有MDO-NPA具有口服活性，且其作用时间比NPA稍长。用氧化酶抑制剂SKF-525A预处理可阻断S(+)MDO-NPA的活性。这些特性与R(-)MDO-NPA的特性相似，我们之前曾报道R(-)MDO-NPA是多巴胺激动剂R(-)NPA的口服活性前药。因此，NPA两种对映体的亚甲二氧基衍生物分别具有潜在临床有用的多巴胺激动剂和边缘多巴胺拮抗剂所需的特性。
