EFFECTS OF SOME 7-ARYLIDENE AND 7-HETEROARYLIDENE MORPHINAN-6-ONES ONTHE ANTINOCICEPTIVE ACTIVITY OF [D-PEN(2), D-PEN(5)]ENKEPHALIN AND [D-ALA(2), GLU(4)]DELTORPHIN-II AND ON MULTIPLE OPIOID RECEPTORS

The in vivo and functional effects of several 7-arylidene and 7-hetero arylidene morphinan-6-ones were determined at the mu-, delta-, and kap pa-opioid receptors using the guinea pig brain membranes, guinea pig i leum (GPI), and mouse vas deferens (MVD). in vivo effects included the antagonism by these compounds given subcutaneously on the antinocicep tive actions of intracerebroventricularly injected [D-Pen(2), D-Pen(5) ]enkephalin (DPDPE) and [D-Ala(2), Glu(4)] deltorphin II (deltorphin I I), the highly selective putative delta(1)- and delta(2)- opioid recep tor agonists. Finally, the partition coefficients of these compounds w ere 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 m ore potent at delta-opioid receptors than at the mu-opioid receptor, w hereas, 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, when the 7-substituents w ere: 1-fluorobenzylidene > benzylidene > 3-pyridylmethylene- > 4-pyrid ylme thylene- > 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-substitu ents were: benzylidene = 1-methyl-2-imidazolylmethylene- > 4-fluoroben zylidene = 3-pyridylmethylene- = 4-pyridylmethylene-. All compounds an tagonized delta(1) and delta(2)-opioid receptor agonist-induced analge sia. The antagonist potencies at the delta(2)-opioid receptor were in the following order, where the 7-substituents were: benzylidene- > 4-c hlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-met hyl-2-imidazolylmethylene- approximate to 4-pyridylmethylene- whereas at the delta(2)-opioid receptor, the order was benzylidene- > 4-chloro benzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2 -imidazolylmethylene- > 4-pyridylmethylene. In general, all compounds exhibited greater potency at the delta(2)- than delta(1)-opioid recept or. The computed partition coefficients were, as expected, greater tha n the apparent log P values, which were determined experimentally. Gen erally, the lipophilicity values in decreasing order were: 4-chloroben zylidene- > 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- = 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene-. In general, th e benzylidene and 4-pyridylmethylene derivatives, which have medium li pophilicities, were equally effective at the delta(1)- and delta(2)- r eceptors; the 3-pyridylmethylene and 1-methyl-2-imidazolylmethylene de rivatives had lower lipophilicities and were more selective for the de lta(2)- than delta(1)- receptor; the 4-chlorobenzylidene and 4-fluorob enzylidene derivatives were more lipophilic and had intermediate activ ity. The plot of pED(50) values for the in vivo tests for the delta(1) - and delta(2)- receptors showed that the two receptors are not indepe ndent with respect to this series of compounds. (C) 1997 Elsevier Scie nce Inc.