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

Abstract Bhargava, H. N., G.-M. Zhao, J.-T. Bian, Y. Nan, S. P. Upadhyaya, X. Wei, W. J. Dunn, III and L. Bauer. Effects of some 7-arylidene and 7-heteroarylidene morphinan-6-ones on the antinociceptive activity of [ d -Pen 2 , d -Pen 5 ] enkephalin and [ d -Ala 2 , Glu 4 ]deltorphin II and on multiple opioid receptors. peptides 18(5) 695–701, 1997.—The in vivo and functional effects of several 7-arylidene and 7-heteroarylidene morphinan-6-ones were determined at the μ -, δ -, and κ -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 -Pen 2 , d -Pen 5 ]enkephalin (DPDPE) and [ d -Ala 2 , Glu 4 ]deltorphin II (deltorphin II), the highly selective putative δ 1 - and δ 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 δ -opioid receptors than at the μ -opioid receptor, whereas, in comparison to the κ -opioid receptor, the activities of the E-7-arylidene or E-7-heteroarylidene naltrexone derivatives at the δ -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 δ -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 δ 1 and δ 2 -opioid receptor agonist-induced analgesia. The antagonist potencies at the δ 1 -opioid receptor were in the following order, where the 7-substituents were: benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolylmethylene- ≈ 4-pyridylmethylene-, whereas at the δ 2 -opioid receptor, the order was benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolylmethylene- > 4-pyridylmethylene. In general, all compounds exhibited greater potency at the δ 2 - than δ 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 δ 1 - and δ 2 - receptors; the 3-pyridylmethylene and 1-methyl-2-imidazolylmethylene derivatives had lower lipophilicities and were more selective for the δ 2 - than δ 1 - receptor; the 4-chlorobenzylidene and 4-fluorobenzylidene derivatives were more lipophilic and had intermediate activity. The plot of pED 50 values for the in vivo tests for the δ 1 - and δ 2 - receptors showed that the two receptors are not independent with respect to this series of compounds.