Effects of some 7-arylidene and 7-heteroarylidene morphinan-6-ones on the antinociceptive activity of [D-Pen2, D-Pen5]enkephalin and [D-Ala2, Glu4]deltorphin II and on multiple opioid receptors.
The in vivo and functional effects of several 7-arylidene and 7-heteroarylidene morphinan-6-ones were determined at the mu-, delta-, and kappa-opioid receptors using the guinea pig brain membranes, guinea pig ileum (GPI), and mouse vas deferens (MVD). In vivo effects included the antagonism by these compounds given subcutaneously on the antinociceptive actions of intracerebroventricularly injected [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2, Glu4]deltorphin II (deltorphin II), the highly selective putative delta 1- and delta 2-opioid receptor agonists. Finally, the partition coefficients of these compounds were estimated (CLOGP) and determined experimentally at pH 7.4 in the 1-octanol/water system. Compared with E-7-benzylidenenaltrexone (BNTX), most compounds except for E-7-(4-chlorobenzylidene)naltrexone, were more potent at delta-opioid receptors than at the mu-opioid receptor, whereas, in comparison to the kappa-opioid receptor, the activities of the E-7-arylidene or E-7-heteroarylidene naltrexone derivatives at the delta-receptor were in the following order, where the 7-substituents were: 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- > 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene > 4-chlorobenzylidene. In the MVD preparation, the potencies at the delta-opioid receptor, in comparison to BNTX, were in the following order, where the 7-substituents were: benzylidene = 1-methyl-2-imidazolylmethylene- > 4-fluorobenzylidene- = 3-pyridylmethylene- = 4-pyridylmethylene-. All compounds antagonized delta 1, and delta 2-opioid receptor agonist-induced analgesia. The antagonist potencies at the delta 1-opioid receptor were in the following order, where the 7-substituents were: benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- approximately 4-pyridylmethylene-, whereas at the delta 2-opioid receptor, the order was benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- > 4-pyridylmethylene. In general, all compounds exhibited greater potency at the delta 2- than delta 1-opioid receptor. The computed partition coefficients were, as expected, greater than the apparent log P values, which were determined experimentally. Generally, the lipophilicity values in decreasing order were: 4-chlorobenzylidene- > 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- = 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene-. In general, the benzylidene and 4-pyridylmethylene derivatives, which have medium lipophilicities, were equally effective at the delta 1- and delta 2-receptors; the 3-pyridylmethylene and 1-methyl-2-imidazolylmethylene derivatives had lower lipophilicities and were more selective for the delta 2- than delta 1-receptor; the 4-chlorobenzylidene and 4-fluorobenzylidene derivatives were more lipophilic and had intermediate activity. The plot of pED50 values for the in vivo tests for the delta 1- and delta 2-receptors showed that the two receptors are not independent with respect to this series of compounds.
Bhargava
H N
HN
Department of Pharmaceutics and Pharmacodynamics, University of Illinois at Chicago 60612, USA. drhnb@uic.edu
Zhao
G M
GM
Bian
J T
JT
Nan
Y
Y
Upadhyaya
S P
SP
Xu
W
W
Dunn
W J
WJ
Bauer
L
L
D000700:Analgesics / Q000037:antagonists & inhibitors*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology*; D009292:Narcotic Antagonists; D009842:Oligopeptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D014018:Tissue Distribution; D014649:Vas Deferens / Q000187:drug effects
D000700:Analgesics; D004745:Enkephalins; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; C060209:deltorphin II, Ala(2)-; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-