COMPARISON OF KAPPA-OPIOIDS IN RHESUS-MONKEYS - BEHAVIORAL-EFFECTS AND RECEPTOR-BINDING AFFINITIES

Bremazocine, [5R-(5,7,8 nyl)1-oxaspiro[4,5]dec-8-yl]-4-benzofuranaceta mide (Cl-977), olidin-1-yl)5-methoxy-1,2,3,4-tetrahydronapth-1-yl benz eneacetamide methanesulfonate (DUP 747), ethylketocyclazocine (EKC), n alorphine, olidinyl)-cyclohexyl]benzo[b]thiophene-4-acetamide (PD11730 2), hyl-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U-50,488), (5, 7,8 ethyl-N[2-(1-pyrrolidinyl),1-oxaspiro[4,5]dec-8-yl benzeneacetamid e (U-69,593) and spiradoline were compared in rhesus monkeys for their discriminative stimulus, analgesic and respiratory effects. Selected compounds also were studied for their binding affinities at mu [[H-3]( D-Ala(2)-Me-Phe(4),Glyol(5))enkephalin], kappa ([H-3]U-69,593) and del ta [[H-3](D-Pen(2)-D-Pen(5)) enkephalin] opioid receptors in monkey br ain membranes. All compounds substituted completely (greater than or e qual to 90%) for EKC in monkeys discriminating between EKC and saline, with the exception that DUP 747 produced a maximum of 74% EKC respond ing. None of the compounds reversed naltrexone responding in morphine- abstinent monkeys; all of the compounds substituted for naltrexone in morphine-treated monkeys discriminating between naltrexone and saline, with the exception that spiradoline produced a maximum of 68% naltrex one responding. Eight compounds produced maximum analgesic effects in a tail withdrawal procedure and quadazocine antagonized these effects; nalorphine did not have analgesic effects, but it antagonized analges ic effects of several other compounds. U-50,488 did not decrease respi ratory function, whereas U-69,593 decreased frequency of respiration a nd volume of respiration to less than 40% of control values; Cl-977, D UP 747, PD117302 and spiradoline had limited effects on respiratory fu nction. Larger doses of each compound increased both respiration and m otor activity. In a receptor binding study, all compounds, with the ex ception of nalorphine, had selectivity for kappa over mu and delta rec eptors. Despite no apparent relationship between affinity for kappa re ceptors in vitro and potency in vivo, all kappa opioids (except nalorp hine) had high affinity for sites labeled by [H-3]U-69,593. Although d emonstrating similarities among these kappa agonists in several behavi oral assays, the current study cannot reject the possible functional s ignificance of kappa receptor subtypes.