Identification and characterization of novel candidate compounds targeting 6‐ and 7‐transmembrane μ‐opioid receptor isoforms

Background and Purpose The μ-opioid receptor (μ receptor) is the primary target for opioid analgesics. 7-transmembrane (TM) 6TM μ isoforms mediate inhibitory excitatory cellular effects. Here, we developed compounds selective 6TM- or 7TM-μ receptors to further our understanding of pharmacodynamic properties receptors. Experimental Approach We performed virtual screening ZINC Drug Now library using in silico 7TM- 6TM-μ structural models identified potential that are and/or Subsequently, characterized most promising candidate functional vitro studies Be2C neuroblastoma transfected cells, behavioural vivo pain assays various knockout mice ex electrophysiology studies. Key Results Our screen 30 compounds. Subsequent shortlisted four (#5, 10, 11 25) demonstrated receptor-dependent NO release. In these also produced dose-dependent hyperalgesic responses. Studies lack specific established nature novel ligands. Ex electrophysiological on spontaneous postsynaptic currents isolated spinal cord slices validated potent (#10) (#5) Conclusion Implications represent a new class ligands will serve as valuable research tools facilitate development opioids with significant analgesic efficacy fewer side-effects.