GR89,696: A Potent κ-Opioid Agonist with Subtype Selectivity in Rhesus Monkeys
- Eduardo R. Butelman1,
- M. C. Holden Ko2,
- John R. Traynor2,
- Jeffrey A. Vivian1,2,
- Mary-Jeanne Kreek1 and
- James H. Woods2,3
- 1Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, New York (E.R.B., M.J.K.); and Departments of2Pharmacology (M.C.H.K., J.T., J.A.V., J.H.W.) and 3Psychology (J.H.W.), University of Michigan, Ann Arbor, Michigan
- Dr. E. R. Butelman, The Rockefeller University (Box 171), 1230 York Ave., New York, NY 10021. E-mail: butelme{at}mail.rockefeller.edu
Abstract
GR89,696 is a synthetic κ-opioid receptor agonist, recently reported to have an agonist profile consistent with selectivity at the proposed “κ2” subtype. The present studies evaluated the effects of GR89,696 in vitro {i.e., in radioligand binding and [35S]guanosine-5′-O-(3-thio)triphosphate assays} and in vivo in rhesus monkeys, in assays used to study κ-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 “κ1” subtype. Overall, GR89,696 displayed the profile of a highly potent κ-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 κ2 receptor subtype.
Footnotes
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↵1 Current Address: Department of Pharmacological and Physiological Sciences, Bowman-Gray School of Medicine, Winston-Salem, NC 27157.
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This study was supported by U.S. Public Health Service Grants DA 01113 (to E.R.B.), DA 05130 (to M.J.K.), DA 00049 (to M.J.K.), and DA 00254 (to J.H.W.).
- Abbreviations:
- EKC
- ethylketocyclazocine
- nor-BNI
- nor-binaltorphimine
- DAMGO
- d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- DPDPE
- [d-Pen2-d-Pen5]-enkephalin
- GTPγS
- guanosine-5′-O-(3-thio)triphosphate
- CHO
- Chinese hamster ovary
- AD50
- concentration of antagonist reversing the effect of DAMGO by 50%
- FR
- fixed ratio
- U69
- U69,593 [(+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide]
- %MPE
- percent maximum possible effect
- ANOVA
- analysis of variance
- CL
- confidence limit
- U50,488
- trans-(+/−)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide
- PT
- pretreatment
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- Received January 5, 2001.
- Accepted May 22, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
