L-365260

This probe, having been disclosed in 1989, was shown to be a selective (~87-fold) antagonist of CCK-B relative to CCK-A. It was also shown to possess reasonable exposure (194 ug/mL at 2 hours) following a 2.5 mg/kg dose, making it a convenient tool compound to use relative to peptide antagonists. The brain penetration of L-365260 is fairly limited relative to some other known benzodiazepines (Brain extraction ratio of 6% relative to benzodiazepine 70%) limiting its use to peripheral in vivo studies. In addition to rat and mice, it has also been studied in pig through iv administration. Despite its widespread use as an in vivo tool compound, the in vitro profiling data for L-365260 is fairly limited, having only been tested against a handful of GPCRs in radioligand binding assays. There is limited information regarding its potential binding on other target classes (ion channels, kinases, etc.). Therefore, while there is a strong pharmacological basis for using this agent as an antagonist given its potency (2 nM) on CCK-B in radioligand binding assays and extensive pharmacological investigations, results using this tool compound should be followed up with orthogonal assays or use of alternative CCK-B antagonists to confirm mechanism of action.