Studies Towards the Synthesis of the Core of Endiandric Acid H
In the presence of a CuBr·SMe2 catalytic system, a very simple and efficient approach for the synthesis of the key precursor of the core of endiandric acids starting from the readily and abundantly available 3-butyn-1-ol in five linear steps with an overall yield of 40% was developed.
Drug Discovery: Structure-led design
Knowing the structures of G-protein-coupled receptors, says Lindau keynote speaker Brian Kobilka, should help with drug development. But how is this progressing?
Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists.
Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first β-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.