Synthesis and pharmacological validation of a novel radioligand for the orphan GPR88 receptor

Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In Vivo Mouse Studies

“…17,18,24−30 A 2019 patent from Pandeia disclosed GPR88 agonists with reasonable potency without the use of a primary amine, which is associated with poor pglycoprotein (PGP) efflux in 2-PCCA and related compounds. 13,15,17,18,29,31 (See 2 in Figure 1 as a representative example. 31 ) Jin et al, published several medicinal chemistry articles on optimizing the structure−activity relationship (SAR) in a series of GPR88 agonists.…”

“…17,18,25−29 They discovered an in vivo probe compound, RTI-13951-33 (3), which has moderate lipophilicity and poor in vivo pharmacokinetic (PK) properties including high in vivo PGP efflux and high clearance. 12,15,18,29 In 2023, the same group announced the discovery of RTI-122 (4), with an improved profile. 17 In their explorations of 3 and 4, Jin et al also demonstrated that both compounds attenuated binge-like alcohol drinking in a murine model.…”

“…All reported GPR88 agonists have a bis-aryl motif on the left-hand side of the molecule, which is associated with increased lipophilicity. ,,− A 2019 patent from Pandeia disclosed GPR88 agonists with reasonable potency without the use of a primary amine, which is associated with poor p-glycoprotein (PGP) efflux in 2-PCCA and related compounds. ,,,,, (See 2 in Figure as a representative example ,,− They discovered an in vivo probe compound, RTI-13951-33 ( 3 ), which has moderate lipophilicity and poor in vivo pharmacokinetic (PK) properties including high in vivo PGP efflux and high clearance. ,,, In 2023, the same group announced the discovery of RTI-122 ( 4 ), with an improved profile . In their explorations of 3 and 4 , Jin et al also demonstrated that both compounds attenuated binge-like alcohol drinking in a murine model. ,, …”