Title: Discovery of aminobenzyloxyarylamides as ## opioid receptor selective antagonists: application to preclinical development of a ## opioid receptor antagonist receptor occupancy tracer.

Abstract: Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for ## opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K(i) = 0.565 nM for ## opioid receptor binding while having a K(i) = 35.8 nM for ## opioid receptors and a K(i) = 211 nM for ## opioid receptor binding. Compound 25 was also a potent antagonist of ## opioid receptors when tested in vitro using a [(35)S]-guanosine 5'O-[3-thiotriphosphate] ([(35)S]GTP-##-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.
(PMID: 21958337)

ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Target ID: 129

ChEMBL target type: Target is a single protein chain