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.