Functionally Selective Dopamine D2/D3 Receptor Agonists Comprising an Enyne Moiety

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• 作者：Christine Hiller ; Ralf C. Kling ; Frank W. Heinemann ; Karsten Meyer ; Harald H眉bner ; Peter Gmeiner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 27, 2013
• 年：2013
• 卷：56
• 期：12
• 页码：5130-5141
• 全文大小：507K
• 年卷期：v.56,no.12(June 27, 2013)
• ISSN：1520-4804

文摘

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 D₂-like receptors. The test compounds were evaluated for their ability to differentially activate distinct signaling pathways. Measurement of D_2L- and D_2S-mediated [³⁵S]GTP纬S incorporation in the presence of coexpressed G伪_o and G伪_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 尾-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 尾-arrestin recruitment compared to G_o coupling.