Pharmacological profiles of fentanyl analogs at mu, delta and kappa opiate receptors.
Receptor binding assays using [3H]DAGO ([D-Ala2,MePhe4-Gly5-ol]enkephalin) (mu), [3H]DPDPE ([D-Pen2,D-Pen5]enkephalin) (delta) and [3H]U-69593 (kappa) were done in guinea pig whole brain membranes. Agonist activity was determined in norbinaltorphimine or beta-funaltrexamine (beta-FNA) treated guinea pig ileum (mu and kappa, respectively) and beta-FNA-treated mouse vas deferens (delta). The compounds with highest affinity were the most potent at the mu-receptor. The selectivity observed in the binding affinities was also found in in vitro activity. No correlation was found between mu-affinity and selectivity; the highest affinity analog, lofentanil, was found to be among the least selective, while another high affinity analog, R30490, was the most mu-selective. The results show that not all fentanyls are highly mu-selective, and could produce actions through delta- and kappa-opiate receptors.
Maguire
P
P
Molecular Research Institute, Palo Alto, CA 94304.
Tsai
N
N
Kamal
J
J
Cometta-Morini
C
C
Upton
C
C
Loew
G
G
D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D044482:Benzeneacetamides; D001921:Brain / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism*; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
D000701:Analgesics, Opioid; D044482:Benzeneacetamides; D004745:Enkephalins; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C051844:norbinaltorphimine; D009271:Naltrexone; C058443:4-methoxymethylfentanyl; C024524:beta-funaltrexamine; C034846:lofentanil; D020881:Enkephalin, D-Penicillamine (2,5)-; C045444:U 69593; D005283:Fentanyl