Functionally Selective Dopamine D2/D3 Receptor Agonists Comprising an Enyne Moiety
Functionally Selective Dopamine D2/D3 Receptor Agonists Comprising an Enyne Moiety
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DOI：
10.1021/jm400520c
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发表时间：
2013-06-27
影响因子：
7.3
通讯作者：
Gmeiner, Peter
中科院分区：
文献类型：
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作者：
Hiller, Christine;Kling, Ralf C.;Gmeiner, Peter
以对映体纯形式合成了1型和2型多巴胺能，并对其代谢稳定性进行了研究。放射配体结合研究表明对d2样受体具有高亲和力。测试化合物被评估其不同激活不同信号通路的能力。在共表达的G α (o)和G α (i)亚基存在的情况下，对D-2L和d - 2s介导的[S-35]GTP γ S掺入的测量显示，几种测试化合物的受体激活显着偏向性。因此，2-偶氮吲哚羧酸酰胺(S)-2a对d - 2s促进的G(o)活化比G(i)偶联具有显著的功能选择性。三唑烷氧基取代苯甲酰胺(S)-2c对G(o)的激活效力高于G在D-2L亚型的偶联效力。在G(i)活化下，联苯基carboxamide (R)-1和2-苯并噻吩基carboxamide (S)-2d对β -捕集蛋白的功能有选择性，而与G(o)偶联相比，2-取代氮杂酚(S)-2a更倾向于β -捕集蛋白。
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 [S-35]GTP gamma S incorporation in the presence of coexpressed G alpha(o) and G alpha(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, coupling at the D-2L subtype. Functional selectivity for beta-arrestin recruitment over G(i) activation was observed for the biphenylcarboxamide (R)-1 and the 2-benzothiophenylcarboxamide (S)-2d, whereas the 2-substituted azaindole (S)-2a preferred beta-arrestin recruitment compared to G(o) coupling.