Functionally selective dopamine D_2/D_3 receptor agonists comprising an enyne moiety

Hiller C.; Kling R.C.; Heinemann F.W.; Meyer K.; Hübner H.; Gmeiner P.

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Functionally selective dopamine D_2/D_3 receptor agonists comprising an enyne moiety

机译：包含烯炔部分的功能选择性多巴胺D_2 / D_3受体激动剂

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Dopaminergics of types 1 and 2 incorporating a conjugated enyne as an atypical catechol-simulating moiety were synthesized in enantiomerically pure form and investigated for their metabolic stability. Radioligand binding studies indicated high affinity to D_2-like receptors. The test compounds were evaluated for their ability to differentially activate distinct signaling pathways. Measurement of D_(2L)- and D_(2S)-mediated [~(35)S]GTPγS incorporation in the presence of coexpressed Gα_o and Gα_i subunits showed significantly biased receptor activation for several test compounds. Thus, the 2-azaindolylcarboxamide (S)-2a exhibited substantial functional selectivity for D_(2S)-promoted G_o activation over G_i coupling. The most significant bias was determined for the triazolylalkoxy-substituted benzamide (S)-2c that displayed higher potency for G_o activation than for G_i coupling at the D_(2L) subtype. Functional selectivity for β-arrestin recruitment over Gi activation was observed for the biphenylcarboxamide (R)-1 and the 2-benzothiophenylcarboxamide (S)-2d, whereas the 2-substituted azaindole (S)-2a preferred β-arrestin recruitment compared to G_o coupling.

机译：以对映体纯的形式合成掺入共轭烯炔作为非典型儿茶酚模拟部分的1型和2型多巴胺能药物，并研究其代谢稳定性。放射性配体结合研究表明对D_2样受体具有高亲和力。评估测试化合物差异激活不同信号途径的能力。在共表达的Gα_o和Gα_i亚基存在下，D_（2L）-和D_（2S）介导的[〜（35）S]GTPγS掺入的测量显示了几种测试化合物的受体活化显着偏向。因此，相对于G_i偶合，2-氮杂吲哚基甲酰胺（S）-2a对D_（2S）促进的G_o活化显示出实质的功能选择性。对于三唑基烷氧基取代的苯甲酰胺（S）-2c，对于D_（2L）亚型的G_o活化表现出比G_i偶联更高的效力，确定了最大的偏差。对于联苯甲酰胺（R）-1和2-苯并硫代苯基甲酰胺（S）-2d，观察到针对Gi活化的β-arrestin募集的功能选择性，而与G_o相比，2-取代的氮杂吲哚（S）-2a更优选β-arrestin募集。耦合。

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《Journal of Medicinal Chemistry》 |2013年第12期|共12页
作者
Hiller C.; Kling R.C.; Heinemann F.W.; Meyer K.; Hübner H.; Gmeiner P.;
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正文语种 eng
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Functionally; dopamine; agonists;

机译：功能上;多巴胺;激动剂;

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1. Functionally selective dopamine D_2/D_3 receptor agonists comprising an enyne moiety [J] . Hiller C., Kling R.C., Heinemann F.W., Journal of Medicinal Chemistry . 2013,第12期

机译：包含烯炔部分的功能选择性多巴胺D_2 / D_3受体激动剂
2. Intrinsic Efficacy of Antipsychotics at Human D_2,D_3,and D_4 Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D_2/D_3 Partial Agonist [J] . E.S.Burstein, J.Ma, S.Wong, The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics . 2005,第3期

机译：抗精神病药对人D_2，D_3和D_4多巴胺受体的内在作用：氯氮平代谢产物N-去甲基氯氮平作为D_2 / D_3部分激动剂的鉴定。
3. Synthesis and Pharmacological Evaluation of Potent and Highly Selective D_3 Receptor Ligands: Inhibition of Cocaine-Seeking Behavior and the Role of Dopamine D_3/D_2 Receptors [J] . Giuseppe Campiani, Stefania Butini, Francesco Trotta, Journal of Medicinal Chemistry . 2003,第18期

机译：高效和高选择性D_3受体配体的合成和药理评价：抑制可卡因的寻找行为和多巴胺D_3 / D_2受体的作用
4. l-stepholidine, a naturally occurring dopamine D1 receptor agonist and D2 receptor antagonist, attenuates methamphetamine self-administration in rate [C] . Kai Yue, BaoMiao Ma, JunQiao Xing International Conference on Applied Sciences, Engineering and Technology . 2014

机译：L- StepHolidine，天然存在的多巴胺D1受体激动剂和D2受体拮抗剂，衰减甲基苯丙胺自我管理
5. Effector selective intrinsic activity of novel dopamine agonists at the D-2 dopamine receptor. [D] . Smith, Hilary Pamela. 1996

机译：新型多巴胺激动剂对D-2多巴胺受体的效应器选择性内在活性。
6. Modification of agonist binding moiety in hybrid derivative 5/7-{2-(4-aryl-piperazin-1-yl)-ethyl-propyl-amino}-5678-tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors [O] . Bhaskar Gopishetty, Suhong Zhang, Prashant S. Kharkar, -1

机译：杂化衍生物5/7-{2-（4-芳基-哌嗪-1-基）-乙基-丙基-氨基} -5678-四氢萘-1-中激动剂结合部分的修饰ol / -2-氨基形式：对多巴胺D2 / D3受体的功能活性和选择性的影响
7. Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity [O] . -1

机译：设计功能性选择性非可解氟乙酯多巴胺D1受体激动剂，具有效力的体内AntiParinsonian活动

Functionally selective dopamine D_2/D_3 receptor agonists comprising an enyne moiety

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