Development of novel alpha 2B adrenergic receptor ligands by using a palladium catalyzed Buchwald Hartwig amination with a brominated benzodiazepine

Some benzodiazepines with excellent affinities to the gamma aminobutyric receptors have been reported to attenuate intracellular calcium by interacting with alpha adrenergic receptors (ARα). To identify novel benzodiazepines that selectively bind adrenergic receptors, we coupled amines to a brominated benzodiazepine starting material, and generated a library of compounds that yielded compounds with good affinity for the ARα₂ subtypes. These compounds were synthesized using a Buchwald Hartwig amination reaction employing XPhos as the most successful ligand among more than twenty ligands that were tested for this purpose and were part of the Catalexis screen platform from Millipore Sigma. The most promising compound has a <i>K</i> _i of 511 nM for the α_2B subtype with a 7.7-fold selectivity over the α_2A and 2.2-fold selectivity over the α_2C adrenergic receptor. Functional cell-based assays identified this compound as an ARα_2B antagonist. All synthesized compounds exhibited a good safety profile <i>in vivo</i> and did not influence sensorimotor coordination and behavior in mice. Overall, these findings confirm the adaptability of the benzodiazepine scaffold in medicinal chemistry enabling future work to fine-tune these compounds to develop a more potent and selective ARα_2B ligand.