GPR61 Inverse agonist 3 

GPR61 Inverse agonist 3 is a selective and brain-penetrant GPR61 inverse agonist with human IC₅₀ of 4.0 nM, mouse IC₅₀ of 8.8 nM, human K_i of 0.34 nM, mouse K_i of 1.1 nM. GPR61 Inverse agonist 3 disrupts GPR61-Gαs protein interactions to abolish GPR61 constitutive activity. GPR61 Inverse agonist 3 moderately inhibits GABA_A chloride channel and PDE3A1 with IC₅₀ values of 4.6 and 8.9 μM. GPR61 Inverse agonist 3 shows no functional effect on food intake in adult mice co-administered with a pan-CYP inhibitor. GPR61 Inverse agonist 3 can be used for the research of cachexia/sarcopenia^[1].

GPR61 Inverse agonist 3 (Compound 23) potently inhibits constitutive activity of human GPR61 in TREx-inducible overexpressed CHO cells with an IC₅₀ of 4.0 nM and binds human GPR61 with a K_i of 0.34 nM^[1].
GPR61 Inverse agonist 3 potently inhibits constitutive activity of mouse GPR61 in overexpressed CHO cells with an IC₅₀ of 8.8 nM and binds mouse GPR61 with a K_i of 1.1 nM^[1].
GPR61 Inverse agonist 3 has moderate MDR1 efflux, low BCRP efflux, good passive permeability, and high intrinsic clearance in human hepatocytes, with respective values of 7.4, 1.2, 32 × 10^-6 cm/s, and 152 μL/min/million cells^[1].
GPR61 Inverse agonist 3 (10 μM) is highly selective for GPR61, with only moderate off-target activity against the GABA_A chloride channel (IC₅₀ = 4.6 μM) and PDE3A1 (IC₅₀ = 8.9 μM), and no significant activity against 104 other targets or tested ion channels^[1].

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

GPR61 Inverse agonist 3 (Compound 23) (300 mg/kg; p.o.; single dose) with ABT (HY-103389) pretreatment does not produce a statistically significant increase in 24-hour cumulative food intake in 10−11 week-old mice^[1].

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

528.96

C₂₁H₂₃ClF₂N₆O₄S

COCCN(S(=O)(C1=CC=C(N=C1OC)NCC2=C(C=NC=C2F)F)=O)C3=NC(C)=C(C(C)=N3)Cl

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• [1]. Fisher EL, et al. Discovery of Potent and Brain-Penetrant Inverse Agonists for GPR61, an Orphan G Protein-Coupled Receptor. J Med Chem. 2026;69(6):7393-7404.  [Content Brief]