title: Structure-based discovery of opioid analgesics with reduced side effects.
abstract: Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent Giactivator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Aashish
authors.initials: A
authors.lastname: Manglik
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA.
authors.forename: Dipendra K
authors.initials: DK
authors.lastname: Aryal
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dengler
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Corder
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Levit
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.|Institut für Physiologie und Pathophysiologie, Paracelsus Medical University, 90419 Nuremberg, Germany.
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Kling
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Viachaslau
authors.initials: V
authors.lastname: Bernat
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Sassano
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Giguère
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
authors.lastname: Da Duan
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Anesthesiology, Perioperative and Pain Medicine, Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Grégory
authors.initials: G
authors.lastname: Scherrer
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D055808:Drug Discovery; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D010146:Pain / Q000188:drug therapy; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D014508:Urea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C586842:((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine; D000701:Analgesics, Opioid; C000614693:PZM21 compound; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D013876:Thiophenes; D014508:Urea; D019206:GTP-Binding Protein alpha Subunits, Gi-Go