Aporphines. 39. Synthesis, dopamine receptor binding, and pharmacological activity of (R)-(-)- and (S)-(+)-2-hydroxyapomorphine.
Aporphines. 39. Synthesis, dopamine receptor binding, and pharmacological activity of (R)-(-)- and (S)-(+)-2-hydroxyapomorphine.
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阿朴啡。
DOI：
10.1021/jm00350a021
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发表时间：
1982
影响因子：
7.3
通讯作者：
Baldessarini,RJ
中科院分区：
文献类型：
--
作者：
Neumeyer,JL;Arana,GW;Ram,VJ;Kula,NS;Baldessarini,RJ
以蒂巴因和布比卡因为原料合成了2，10，11-三羟基阿朴啡（TEA）的对映体（6aS和6aS），并通过与氚化阿朴吗啡、ADTN和螺哌利多竞争结合小牛尾状核的膜部分以及刺激腺苷酸环化酶的能力，与（-）-阿朴吗啡[（-）-APO]和多巴胺进行了体外比较。在所有四个测试中，效力的等级顺序为㈠-APO> ㈠-THA>（+）-THA。因此，这些结果扩展了羟基阿朴啡的6-羟基构型对于与假定的多巴胺受体的相互作用是优选的以及与10，11-二羟基阿朴啡相比2-羟基化降低了效力的印象。自从在羟基化阿朴啡衍生物如阿朴吗啡中发现治疗上有用的多巴胺（DA）激动剂活性以来，[3]在描绘阿朴啡分子结构中负责多巴胺能特性和与DA受体相互作用的部分方面，已经引起了相当大的兴趣。4，5如果受体及其与活性物质相互作用的模式在精确的分子细节中得到了解，药物设计的过程可以大大改进。然后，这些信息可以用来设计构象定义的结构，其中药效基团在适当的空间排列中定向，以实现最佳的受体相互作用。由于DA是一种非手性和构象灵活的分子，与DA受体的相互作用的信息很少，可以得到这种神经递质。阿扑吗啡[（-）-！，Saari等人6报道了通过吗啡的酸催化重排获得的对映异构体[（-）-APO]是多巴胺能和催吐活性的活性对映异构体。阿扑吗啡的S（+）对映体在单侧尾状核损伤小鼠中显示出不产生姿势不对称。6尽管阿扑吗啡与假定的DA受体的相互作用复杂，并且阿扑吗啡在DA系统（包括中枢神经系统）中作为可能的部分激动剂或混合激动剂/拮抗剂的状态复杂，7 - 10阿扑吗啡分子已经作为研究DA受体相互作用的良好起点。这一建议得到了
The enantiomers (6afi and 6aS) of 2, 10, 11-trihydroxyaporphine (TEA) were synthesized from thebaine and bul-bocapnine and evaluated pharmacologically in vitro in comparison with (-)-apomorphine [(-)-APO] and dopamine by competitionwith tritiated apomorphine, ADTN, and spiroperidolfor binding to a membrane fractionof calf caudate nucleus, as well as for ability to stimulate adenylate cyclase. In all four tests, the rank order of potency was (-)-APO>(-)-THA»(+)-THA. Thus, these results extend the impression that the 6afi configuration for hydroxyaporphines is preferred for interactions with putative dopamine receptors and that 2-hydroxylation reduces potency in comparison with 10, 11-dihydroxyaporphinesSince the discovery of therapeuticallyuseful dopamine (DA) agonist activity in hydroxylatedaporphine derivatives, such as apomorphine, 3** considerable interest has developed in delineating the portions of the aporphine molecular structure responsible for dopaminergic prop-erties and the interactions with DA receptors. 4, 5 The process of drug design could be considerably improved if receptors and their mode of interaction with active substances were known in precise molecular detail. Such information could then be used to design conformationally defined structures in which pharmacophoric groups are oriented in the appropriate spatial arrangement for optimal receptor interaction. Since DA is an achiral and conformationally flexible molecule, little information concerning interactions with DA receptors can be obtained with this neurotransmitter. Apomorphine [(-)-!,(-)-APO], the enantiomer obtained by the acid-catalyzed rearrangement of morphine, was reported by Saari et al. 6 to be the active enantiomer for dopaminergic and emetic activity. The S (+) enantiomer of apomorphine was shown to be inactive in producing postural asymmetries in unilaterally cau-date-lesioned mice. 6 Despite the complexities of inter-actions of apomorphine with presumed DA receptors and the status of apomorphine as a possible partial agonist or mixed agonist/antagonist in DA systems, including those in the central nervous system, 7" 10 the apomorphine molecule has served as a good starting point for the study of DA receptor interactions. This proposal is supported by