Photosensitized regeneration of carbonyl compounds from oximes

[reaction: see text] Deprotection of oximes to their corresponding carbonyl compounds through the use of photosensitized electron-transfer reactions proceeds in reasonable to good yields. Better yields are obtained in nonpolar solvents and when triplet sensitizers are used. Preliminary mechanistic studies suggest the involvement of an iminoxyl radical.     

Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor

G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β₂ adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets.