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

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 D2L- and D2S-mediated [35S]GTPγS incorporation in the presence of coexpressed Gαo and Gαi subunits showed significantly biased receptor activation for several test compounds. Thus, the 2-azaindolylcarboxamide (S)-2a exhibited substantial functional selectivity for D2S-promoted Go activation over Gi coupling. The most significant bias was determined for the triazolylalkoxy-substituted benzamide (S)-2c that displayed higher potency for Go activation than for Gi coupling at the D2L 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 Go coupling.