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 upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon 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.

Figure 1

Comparison of the effects of chronic drug treatment on DAMGO-mediated inhibition of forskolin-stimulated cAMP accumulation in MOR/DOR dimer cells: MOR/DOR dimer cells were treated for 20 h with morphine (1 µM), or 17d (30 nM), or 17h (30 nM), respectively. DAMGO-mediated inhibition of forskolin-stimulated cAMP accumulation was performed as described in Methods section. Data are presented as the EC₅₀ ratio (fold over control). Each value is the mean ± SEM (n=3). *p<0.05 when compared with the control cells (two-tailed Student’s t-test).

Figure 2

Comparison of the effects of chronic drug treatment on spontaneous and naloxone (10 µM)-induced cAMP overshoot in MOR/DOR dimer cells: MOR/DOR dimer cells were treated for 20 h with morphine (1 µM), or 17d (30 nM), or 17h (30 nM), respectively. The forskolin-stimulated cAMP accumulation was assessed as described in Methods. Each value is the mean ± SEM (n=3). *p<0.05 when compared with no addition condition of the control cells. #p<0.05 when compared with no addition condition of the morphine-treated or 17h-treated cells (two-tailed Student’s t-test).

Figure 3

Antinociceptive dose– and time–response curves for 17d and 17e in the 55 °C warm-water tail-withdrawal assay.

Figure 4

Antinociceptive dose–response curves for naive control mice and mice injected repeatedly with A₉₀ doses of 17d (left panel) or morphine (right panel) i.c.v. twice daily for 3 days.

Scheme 1

Synthesis of 14-Alkoxypyridomorphinans 17a–ha ^aReagents and conditions: (a) NaH, DMF, Me₂SO₄ or R′Br, 0 °C to rt; (b) BBr₃, CH₂Cl₂, −78 °C to rt.

Scheme 2

Synthesis of 14-Acyloxypyridomorphinans 18a–f and 21–23a ^aReagents and conditions: (a) R′COCl, Et₃N, DMF or PhMe; (b) K₂CO₃, MeOH-H₂O, rt; (c) PhCOCl, Et₃N, DMF.

Chart 1^a

^aCPM = cyclopropylmethyl