Bremazocine, [5R-(5,7,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)1-ox- aspiro[4,5]dec-8-yl]-4-benzofuranacetamide (Cl-977), (±)-trans-3,4-dichloro- N-methyl-(2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetrahydronapth-1-yl benzeneacetamide methanesulfonate (DUP 747), ethylketocyclazocine (EKC), nalorphine, (±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzo[b]thiophene-4-acetamide (PD117302), trans-(±)-3,4-dichloro- N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U-50,488), (5,7,8β)-N-methyl-N[2-(1-pyrrolidinyl), 1-oxaspiro[4,5]dec-8-yl benzeneacetamide (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 [[3H](D-Ala2-Me-Phe4,Glyol5)enkephalin], kappa ([3H]U-69,593) and delta [[3H](D-Pen2-D-Pen5) enkephalin] opioid receptors in monkey brain membranes. All compounds substituted completely (≥ 90%) for EKC in monkeys discriminating between EKC and saline, with the exception that DUP 747 produced a maximum of 74% EKC responding. 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% naltrexone 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 analgesic effects of several other compounds. U-50,488 did not decrease respiratory function, whereas U-69,593 decreased frequency of respiration and volume of respiration to less than 40% of control values; Cl-977, DUP 747, PD117302 and spiradoline had limited effects on respiratory function. Larger doses of each compound increased both respiration and motor activity. In a receptor binding study, all compounds, with the exception of nalorphine, had selectivity for kappa over mu and delta receptors. Despite no apparent relationship between affinity for kappa receptors in vitro and potency in vivo, all kappa opioids (except nalorphine) had high affinity for sites labeled by [3H]U-69,593. Although demonstrating similarities among these kappa agonists in several behavioral assays, the current study cannot reject the possible functional significance of kappa receptor subtypes.
|Original language||English (US)|
|Number of pages||12|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1994|
ASJC Scopus subject areas
- Molecular Medicine