GPR120-IN-1

This probe (cpdA) was demonstrated to show excellent cellular activity on and submicromolar activity in a cellular beta-arrestin interaction assay in GPR120-transfected cells. In vivo, the probe was found to exhibit beneficial metabolic effects in a standard high fat-fed obese mouse model, including anti-inflammatory effects on macrophages both in vitro and in vivo, improved glucose tolerance, and increased insulin sensitivity. The fact that the probe completely lacked Ca++ mobilization activity in a GPR40 (FFAR1) overexpressing cell line, and did not have appreciable in vivo metabolic effects in a GPR120 knockout mouse provides strong evidence that the published phenotypic effects of cpdA are due to on-target agonistic activity of GPR120. Moreover, because this compound has a highly drug-like scaffold and has in vivo activity through PO administration, it is, therefore, a valuable and recommended probe to use in a variety of settings. No biochemical binding data has been published for this probe, likely because of the challenges in developing the relevant assays for this target class. Because its activity against other target classes has not been published, additional confirmatory studies for cpdA are likely necessary to conclusively prove on-mechanism activity in other applications. Finally, because no pharmacokinetic data have been published for cpdA, care must be taken when adjusting doses in mice or when dosing in other species (e.g. diabetic or obese rats).

There is insufficient off-target data on the compound and no raw data were supplied to assess the efficacy and potency of the compound of interest. Without a negative control as well as comprehensive off-target profiling it is not recommended using this probe.

Up to 500 micromoles/L of GPR120-IN-1 can be applied topically to the mouse tongue to stimulate fatty acid taste reception; Yasumatsu et al. (doi:10.111/apha.13215) have established, using GPR120 knockout mice, that such application of GPR120-IN-1 to the mouse tongue can elicit chorda tympani nerve responses only in wildtype mice, thereby independently establishing the target of GPR120-IN-1 as GPR120.