title: 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.
authors.affiliation: Organic Chemistry Department, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ananthan
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Saini
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGlinchey
authors.forename: Denise
authors.initials: D
authors.lastname: Giuvelis
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004361:Drug Tolerance; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000209:etiology*; D011725:Pyridines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000819:agonists*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C577114:5'-(4-chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-4,5-epoxy-3-hydroxy-14-(3-phenylpropoxy)pyrido(2',3'-6,7)morphinan; D000701:Analgesics, Opioid; D009019:Morphinans; D011725:Pyridines; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D009020:Morphine; D000242:Cyclic AMP