title: GR89,696: a potent kappa-opioid agonist with subtype selectivity in rhesus monkeys.
abstract: GR89,696 is a synthetic kappa-opioid receptor agonist, recently reported to have an agonist profile consistent with selectivity at the proposed "kappa(2)" subtype. The present studies evaluated the effects of GR89,696 in vitro (i.e., in radioligand binding and [(35)S]guanosine-5'-O-(3-thio)triphosphate assays) and in vivo in rhesus monkeys, in assays used to study kappa-opioid agonists (i.e., thermal antinociception, sedation and muscle relaxation, diuresis, and increases in serum prolactin levels, as well as ethylketocyclazocine and U69,593 discrimination). Furthermore, the sensitivity of GR89,696 to naltrexone and nor-binaltorphimine (nor-BNI) antagonism was compared with that of U50,488 and U69,593, ligands selective for the proposed "kappa(1)" subtype. Overall, GR89,696 displayed the profile of a highly potent kappa-opioid agonist, following parenteral administration in rhesus monkeys. GR89,696 was less sensitive than U50,488 and U69,593 to naltrexone or nor-BNI antagonism, consistent with an action through the proposed kappa(2) receptor subtype.
authors.affiliation: Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10021, USA. butleme@mail.rockefeller.edu
authors.forename: E R
authors.initials: ER
authors.lastname: Butelman
authors.forename: M C
authors.initials: MC
authors.lastname: Ko
authors.forename: J R
authors.initials: JR
authors.lastname: Traynor
authors.forename: J A
authors.initials: JA
authors.lastname: Vivian
authors.forename: M J
authors.initials: MJ
authors.lastname: Kreek
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004192:Discrimination, Psychological / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D016314:Ethylketocyclazocine / Q000494:pharmacology; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011388:Prolactin / Q000097:blood; D011759:Pyrrolidines / Q000494:pharmacology*; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D044482:Benzeneacetamides; D010879:Piperazines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C116587:kappa(1) opioid receptor; C108819:kappa(2) opioid receptor; C071609:GR 89696; C051844:norbinaltorphimine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D016314:Ethylketocyclazocine; D009271:Naltrexone; D011388:Prolactin; C045444:U 69593