title: Identification of selective agonists and positive allosteric modulators for µ- and δ-opioid receptors from a single high-throughput screen.
abstract: Hetero-oligomeric complexes of G protein-coupled receptors (GPCRs) may represent novel therapeutic targets exhibiting different pharmacology and tissue- or cell-specific site of action compared with receptor monomers or homo-oligomers. An ideal tool for validating this concept pharmacologically would be a hetero-oligomer selective ligand. We set out to develop and execute a 1536-well high-throughput screen of over 1 million compounds to detect potential hetero-oligomer selective ligands using a β-arrestin recruitment assay in U2OS cells coexpressing recombinant µ- and δ-opioid receptors. Hetero-oligomer selective ligands may bind to orthosteric or allosteric sites, and we might anticipate that the formation of hetero-oligomers may provide novel allosteric binding pockets for ligand binding. Therefore, our goal was to execute the screen in such a way as to identify positive allosteric modulators (PAMs) as well as agonists for µ, δ, and hetero-oligomeric receptors. While no hetero-oligomer selective ligands were identified (based on our selection criteria), this single screen did identify numerous µ- and δ-selective agonists and PAMs as well as nonselective agonists and PAMs. To our knowledge, these are the first µ- and δ-opioid receptor PAMs described in the literature.
authors.affiliation: Leads Discovery and Optimization, Bristol-Myers Squibb Company, Wallingford, CT, USA neil.burford@bms.com.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Burford
authors.affiliation: DiscoveRx Corporation, Fremont, CA, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Wehrman
authors.affiliation: DiscoveRx Corporation, Fremont, CA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bassoni
authors.affiliation: FORMA Therapeutics, Watertown, MA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: O'Connell
authors.affiliation: Leads Discovery and Optimization, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Martyn
authors.initials: M
authors.lastname: Banks
authors.affiliation: Leads Discovery and Optimization, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Leads Discovery and Optimization, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D009292:Narcotic Antagonists / Q000494:pharmacology; D055503:Protein Multimerization; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000737:chemistry*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000737:chemistry*; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; D019390:Arrestins; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D000071557:beta-Arrestins; D005576:Colforsin; D000242:Cyclic AMP
keywords: GPCR; high-throughput screen; opioid receptor; positive allosteric modulator; β-arrestin