科研之友
微信
新浪微博
Facebook
分享链接
摘要
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.
- 出版日期2013-6-27
