PF-592379

Bitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in an improvement of receptor selectivity, potency, and efficacy. In particular, for both agonists and antagonists of the dopamine D2 and D3 receptors (D2R and D3R), the primary therapeutic targets for several neurological and neuropsychiatric disorders, bitopic ligand design has proved advantageous in achieving better pharmacological profiles in vitro. Although the two pharmacophores within a bitopic ligand are typically considered the main drivers of conformational change for a receptor, the role of the linker that connects the two has not yet been systematically studied for its relevance in receptor activity profiles. Here, we present a comprehensive analysis of sumanirole and PF592,379-based indole-containing bitopic compounds in agonist activity at D2R and D3R, with a focus on linker chemical space and stereochemistry through testing six distinct chirally resolved linkers and a simple aliphatic linker. The structure activity relationships (SARs) of these linkers are examined extensively, beyond the conventional level, by characterizing the activation of all putative transducers over a 44 min time course. Our multiparametric analysis reveals previously unappreciated specific linker-dependent effects on primary pharmacophores, receptors, transducer activation kinetics, and bias, highlighting the utility of this comprehensive approach and the significance of the linker type in shaping transducer bias profiles.