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The 7\u2010transmembrane (TM) and 6TM \u03bc receptor isoforms mediate inhibitory and excitatory cellular effects. Here, we developed compounds selective for 6TM\u2010 or 7TM\u2010\u03bc receptors to further our understanding of the pharmacodynamic properties of \u03bc receptors.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We performed virtual screening of the ZINC Drug Now library of compounds using in silico 7TM\u2010 and 6TM\u2010\u03bc receptor structural models and identified potential compounds that are selective for 6TM\u2010 and\/or 7TM\u2010\u03bc receptors. Subsequently, we characterized the most promising candidate compounds in functional in vitro studies using Be2C neuroblastoma transfected cells, behavioural in vivo pain assays using various knockout mice and in ex vivo electrophysiology studies.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Our virtual screen identified 30 potential candidate compounds. Subsequent functional in vitro cellular assays shortlisted four compounds (#5<\/jats:bold>, 10<\/jats:bold>, 11<\/jats:bold> and 25<\/jats:bold>) that demonstrated 6TM\u2010 or 7TM\u2010\u03bc receptor\u2010dependent NO release. In in vivo pain assays these compounds also produced dose\u2010dependent hyperalgesic responses. Studies using mice that lack specific opioid receptors further established the \u03bc receptor\u2010dependent nature of identified novel ligands. Ex vivo electrophysiological studies on spontaneous excitatory postsynaptic currents in isolated spinal cord slices also validated the hyperalgesic properties of the most potent 6TM\u2010 (#10<\/jats:bold>) and 7TM\u2010\u03bc receptor (#5<\/jats:bold>) ligands.<\/jats:p><\/jats:sec>Conclusion and Implications<\/jats:title>Our novel compounds represent a new class of ligands for \u03bc receptors and will serve as valuable research tools to facilitate the development of opioids with significant analgesic efficacy and fewer side\u2010effects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15463","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T05:22:35Z","timestamp":1617081755000},"page":"2709-2726","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identification and characterization of novel candidate compounds targeting 6\u2010 and 7\u2010transmembrane \u03bc\u2010opioid receptor 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