NF-56-EJ40 

NF-56-EJ40 is a potent, high-affinity, and highly selective human SUCNR1 (GPR91) antagonist with an IC₅₀ of 25 nM and a K_i of 33 nM, and shows almost no activity towards rat SUCNR1. NF-56-EJ40 has high affinity for humanized rat SUCNR1 with a K_i value of 17.4 nM^[1].

SUCNR1 (GPR91)^[1]

NF-56-EJ40 is bound deep inside the hydrophobic pocket, with the acid group coordinated by the hydroxyl groups of the conserved residues Y83^2.64 and Y30^1.39 on one side, and R281^7.39 on the other side. The conserved E18^1.27 is predicted to form an additional hydrogen bond to the piperazine ring of NF-56-EJ40. E22^1.31 and N274^7.32 in human SUCNR1 are replaced by K181.31 and K269^7.32 in rat SUCNR1. These two amino acid exchanges could prevent the binding of NF-56-EJ40 to rat SUCNR1 owing to steric hindrance. Radioligand-binding studies with human SUCNR1 showed partial agreement with our homology model: the Y30^1.39F mutant of human SUCNR1, shows reduced binding of NF-56-EJ40. Similar effects are observed with the E18^1.27K and E18^1.27R mutants, probably owing to steric clashes of the Lys and Arg residues with NF-56-EJ40 and the loss of a hydrogen bond to its piperazine ring^[1].
? Human SUCNR1 residues are introduced into rat SUCNR1 to form the double mutant K18^1.31E/K269^7.32N (hereafter denoted humanized rat SUCNR1) (K_i of 17.4 nM and 33.5 nM for human and humanized rat SUCNR1, respectively). NF-56-EJ40 increases the thermal stability of both humanized rat SUCNR1 and human SUCNR1, but not that of rat SUCNR1^[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

443.54

C₂₇H₂₉N₃O₃

2380230-73-7

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• [1]. Haffke M, et al. Structural basis of species-selective antagonist binding to the succinate receptor. Nature. 2019 Oct;574(7779):581-585.  [Content Brief]