title: Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects.
abstract: It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3-10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , WDH 8-114, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors: Morgan
authors: M
authors: Le Naour
authors: Mary M
authors: MM
authors: Lunzer
authors: Michael D
authors: MD
authors: Powers
authors: Alexander E
authors: AE
authors: Kalyuzhny
authors: Michael A
authors: MA
authors: Benneyworth
authors: Mark J
authors: MJ
authors: Thomas
authors: Philip S
authors: PS
authors: Portoghese
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001362:Avoidance Learning / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004361:Drug Tolerance; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D009271:Naltrexone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D055503:Protein Multimerization; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019966:Substance-Related Disorders / Q000209:etiology; D000071557:beta-Arrestins
chemical_list: C000594989:17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-((2'-indolyl)acetamido)morphinan; D000700:Analgesics; D019390:Arrestins; D007211:Indoles; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D000071557:beta-Arrestins; D009271:Naltrexone; D002118:Calcium