14-Alkoxy- and 14-Acyloxypyridomorphinans: μ Agonist/δ Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects

Abstract

In the search for opioid ligands with mixed functional activity, a series of 5′-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects on prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine on repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence and related side effects.

The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence

“…Opioids which produce tolerance and dependence such as morphine induce an IC 50 tolerance shift in vitro after chronic treatment, as well as super-activation of baseline cAMP levels, at both mu and delta receptors (Avidor-Reiss et al 1995; Varga et al 2003). Drugs that do not induce these in vitro markers of tolerance and dependence are correlated with reduced tolerance and dependence in vivo (Ananthan et al 2012). Surprisingly, MMP-2200 induced a tolerance shift and cAMP super-activation greater than or equal to morphine at both mu and delta receptors (Fig.…”

“…For the mu, the drug concentrations were 25 fold of the EC 50 value (5 μM for MMP-2200, 1 μM for morphine), and for the delta, 5 fold of the EC 50 value for MMP-2200 (70 nM), and a non-normalized concentration of 10 μM for morphine. These normalized concentrations were established by empirical testing, and based off of earlier cAMP tolerance work (data not shown, Ananthan et al 2012). …”

Molecular Pharmacology ofδ-Opioid Receptors

“…The hydroxymorphinan-derived pyridomorphinan SoRI 20411 [59-(4-Chlorophenyl)-6,7-didehydro-4,5a-epoxy-3-hydroxy-17-methylpyrido [29,39: 6,7]morphinan] is a MOPr agonist/DOPr antagonist with approximately 10-fold lower antinociceptive potency than morphine (intracerebroventricular administration) and with low propensity to produce analgesic tolerance (Ananthan et al, 2004). Compared with the latter compound, the 14-alkoxypyridomorphinan SoRI 22138 [59-(4-Chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3-hydroxy-14-(3-phenylpropoxy)pyrido [29,39:6,7]morphinan] is a more potent and more balanced MOPr agonist/DOPr antagonist (Ananthan et al, 2012) (Fig. 11).…”

Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors

“…DAMGO, natrindole, trans-(Ϯ) -3,4- (CHO-hKOR cell line) were generated as described previously (42). The CHO-hMOR cell line was a gift from Dr. Richard B. Rothman of the National Institute on Drug Abuse (43). The CHO-hDOR cell line was made by stably transfecting CHO cells with human DOR cDNA (Missouri S&T cDNA Resource Center, Rolla, MO).…”