Figure 1. Structure based ligand discovery for the μOR.

a, Opiate-induced μOR signalling through G_i activates G-protein-gated inwardly rectifying potassium channels (GIRKs) and inhibits adenylyl cyclase, leading to analgesia. Conversely, recruitment of β-arrestin is implicated in tolerance, respiratory depression, and constipation. b, Cutaway of the μOR orthosteric site to which β-FNA binds. Highlighted regions on the extracellular side diverge between the opioid receptors. c, Conserved features of opioid ligand recognition in the μOR. d, Overlaid docking poses of 23 compounds selected for experimental testing. e, Single-point competition binding assay of 23 candidate molecules against the μOR antagonist ³H-diprenorphine. Each ligand was tested at 20 μM and for those with > 25% inhibition affinity was calculated in full displacement curves; data represent mean ± s.e.m. (n = 3 measurements). One of these hits, compound 7, was subsequently optimized. f, Docking pose of compound 7.