Costall B, Naylor R J
J Med Chem. 1977 Feb;20(2):190-6. doi: 10.1021/jm00212a002.
The synthesis and physical properties of 8-hydroxyaporphine (3a) and 8-hydroxy-N-n-propylnoraporphine (3b) are described. The replacement of the rigid aporphine ring system by the more flexible benzyltetrahydroisoquinoline moiety, still containing all the necessary substitutents of the potent dopamine agonist N-n-propylnorapomorphine (1b) (NPA), resulted in the synthesis of 1-(3,4-dihydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (4). Analogous to 4,1-(4-hydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (5) was synthesized for a direct comparison with the biological activity of the corresponding 10-hydroxyaporphine (2). All compounds synthesized were evaluated as salts of their racemates. In animals with unilateral 6-OHDA lesion of the nigrostriatal pathway, (-)NPA and 2 caused dose-dependent contralateral circling behavior although activity was greatly reduced for the monohydroxylated aporphine 2. 3b,4, and 5 were inactive at doses of 0.25-4.0 mg/kg sc. Compounds 2 and 3b exhibited very weak activity in the stereotype tests in comparison to the response obtained with apomorphine and (-)-NPA. 4 and 5 failed to induce any sterotyped response. These compounds were also investigated for their ability to stimulate locomotor activity following direct injection into the nucleus accumbens. (-)-NPA induced a modest increase in activity but apomorphine completely failed to elicit a locomotor responses and antagonized the effect induced by dopamine. 2,3b, 4 and 5 neither enhanced locomotor activity on direct injection into the nucleus accumbens nor antagonized the hyperactivity response to intraacumbens dopamine when administered peripherally. On direct injection into the caudate-putamen only apomorphine induced stereotyped biting; (-)-NPA, 2, 3b, 4, and 5 were inactive. The differential activity of the aporphine derivatives in these tests strongly supports the possible existence of different types of dopamine receptors within the extrapyramidal and mesolimbic systems. The present studies confirm that the flexible benzylisoquinolines 4 and 5 do not adopt the active dopamine conformation and that the rigid aporphines, preferably containing hydroxyl functions at the 10 or 11 positions, are of greater importance in eliciting potent dopamine agonist activity.
本文描述了8-羟基阿朴啡（3a）和8-羟基-N-正丙基去甲阿朴啡（3b）的合成及其物理性质。用更具柔性的苄基四氢异喹啉部分取代刚性的阿朴啡环系，该部分仍含有强效多巴胺激动剂N-正丙基去甲阿朴吗啡（1b）（NPA）的所有必要取代基，从而合成了1-(3,4-二羟基苄基)-2-丙基-1,2,3,4-四氢异喹啉（4）。与化合物4类似，合成了1-(4-羟基苄基)-2-丙基-1,2,3,4-四氢异喹啉（5），以便与相应的10-羟基阿朴啡（2）的生物活性进行直接比较。所合成的所有化合物均以其外消旋体的盐进行评估。在黑质纹状体通路单侧6-OHDA损伤的动物中，(-)-NPA和2引起剂量依赖性的对侧转圈行为，尽管单羟基化的阿朴啡2的活性大大降低。3b、4和5在0.25 - 4.0mg/kg皮下注射剂量时无活性。与阿朴吗啡和(-)-NPA相比，化合物2和3b在刻板行为试验中表现出非常弱的活性。4和5未能诱导任何刻板反应。还研究了这些化合物直接注射到伏隔核后刺激运动活性的能力。(-)-NPA引起适度的活性增加，但阿朴吗啡完全未能引发运动反应，并拮抗多巴胺诱导的效应。2、3b、4和5直接注射到伏隔核中既不增强运动活性，外周给药时也不拮抗对伏隔核内多巴胺的多动反应。直接注射到尾状核-壳核中时，只有阿朴吗啡诱导刻板咬行为；(-)-NPA、2、3b、4和5无活性。阿朴啡衍生物在这些试验中的不同活性有力地支持了锥体外系和中脑边缘系统中可能存在不同类型多巴胺受体的观点。本研究证实，柔性的苄基异喹啉4和5不具有活性多巴胺构象，而刚性的阿朴啡，最好在10或11位含有羟基官能团，在引发强效多巴胺激动剂活性方面更为重要。
