Discovery and characterization of a novel series of D2 dopamine receptor‐selective antagonists though iterative chemistry of a BET bromodomain inhibitor

Recent findings by several groups have highlighted the potential for targeting D2 dopamine receptors (D2R) in cancer pharmacotherapy. In addition to being an important therapeutic target for psychiatric disorders (all current FDA‐approved antipsychotics are D2R antagonists), it has been proposed that D2Rs are over‐expressed in several types of cancer and that D2R inhibition is associated with anti‐proliferative effects. In developing therapeutic compounds which target bromodomain (BET) proteins (well‐known cancer targets whose inhibitors are known to synergize with multiple classes of drugs), we have found compounds that unexpectedly exhibited both BET inhibition and D2R antagonism. The lead compound, CG250, displays high affinity for BET (~32 nM) as well as the D2R (~80 nM) and ~50‐fold selectivity vs. the D3R and D4R in radioligand competition binding assays. These initial findings of moderately selective D2R antagonism within this core scaffold led us to develop other analogs around this series to examine D2R selectivity. A library of CG250 analogs (~100 compounds) were synthesized to examine the structure‐activity relationships underlying D2R‐antagonism. This library was analyzed for D2R, D3R, and D4R binding activities using competition radioligand binding assays, functional signaling readouts (β‐arrestin recruitment and cAMP inhibition), and BET inhibition. These analogs had varying potencies for D2R antagonism and BET inhibition, including some analogs that were selective for one activity or the other. Lead analog CG14274 displayed high affinity for the D2R (<100 nM) and >400‐fold selectivity vs. the D3R in competition binding and β‐arrestin recruitment assays. Functional profiling of the CG14274 scaffold against a large (168) panel of diverse GPCRs revealed global selectivity in that it was only active in antagonizing a D2R‐mediated response. Given the striking selectivity and potency of CG14274, further development and a focused medicinal chemistry campaign of this lead compound is warranted. Optimization of this series will allow for rational drug design strategies that may result in the development of novel D2R‐selective antagonists or dual BET/D2R inhibitors for the treatment of psychiatric disorders and/or cancer. Support or Funding Information NINDS IRP This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .