The antipsychotic dopamine 2 receptor antagonist diphenylbutylpiperidines improve glycemia in experimental obesity by inhibiting succinyl-CoA:3-ketoacid CoA transferase

Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D), it remains difficult to manage. Hence, new therapeutic options targeting unique mechanisms of action are required. We have previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone oxidation, contributes to the hyperglycemia characterizing obesity and T2D. Moreover, we identified that the typical antipsychotic agent, pimozide, is a SCOT inhibitor that can alleviate obesity-induced hyperglycemia. We have now extended those observations herein, using computer-assisted in silico modelling and in vivo pharmacology studies that highlight SCOT as a noncanonical target shared amongst the diphenylbutylpiperidine (DPBP) drug class, which includes penfluridol and fluspirilene. All 3 DPBPs tested (pimozide, penfluridol, and fluspirilene) improved glycemia in obese mice. While the canonical target of the DPBPs is the dopamine 2 receptor, studies in obese mice demonstrated that acute or chronic treatment with a structurally unrelated antipsychotic dopamine 2 receptor antagonist, lurasidone, was devoid of glucose-lowering actions. We further observed that the DPBPs improved glycemia in a SCOT-dependent manner in skeletal muscle, suggesting that this older class of antipsychotic agents may have utility in being repurposed for the treatment of T2D.