Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes.
The binding parameters of radiolabeled DAMGO (mu), DPDPE and pCl-DPDPE (delta) and 5 alpha, 7 alpha, 8 beta-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]benzeneacetamide (also known as U69593, kappa) and the affinity and selectivity profiles of various opioid agonists and antagonists at the three opioid receptor types were determined in membranes from brain cortex of rhesus monkey. Among the 10 opioids with established mu-selective actions, etonitazene inhibited the binding of [3H]DAMGO with a Ki of 0.02 nM (0.01 nM without sodium) and exhibited mu/delta and mu/kappa selectivities of 8800 and 11,650, respectively. DAMGO had a Ki of 1.23 nM and was about 500-fold more selective at mu receptors compared with delta and kappa sites. Other mu opioids with higher than 100-fold binding selectivity were fentanil and sufentanil. Highly selective delta opioids were DPDPE, deltorphin II and naltrindole. With the exception of N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, all investigated putative delta opioids bound to delta sites with low Kis, i.e., 0.04 nM, 0.13 nM and 1.4 nM for naltrindole, (+/-)-4-[(alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl) -3- hydroxybenzyl]-N,N-diethylbenzamide and DPDPE, respectively. In this series, the displacement of [3H]pCl-DPDPE yielded results similar to those obtained with [3H]DPDPE. With nanomolar Kis of 0.70, 0.89, 0.25 and 0.06, respectively, the highest kappa selectivity was displayed by (trans)-(+/-)-3,4-dichloro-N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide and U69593, followed by dynorphin 1-13 and norbinaltorphimine.(ABSTRACT TRUNCATED AT 250 WORDS)
Emmerson
P J
PJ
Department of Pharmacology, University of Michigan Medical School, Ann Arbor.
Liu
M R
MR
Woods
J H
JH
Medzihradsky
F
F
D000818:Animals; D001921:Brain / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009294:Narcotics / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004745:Enkephalins; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-