Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 18. N-Substituted 14-Phenylpropyloxymorphinan-6-ones with Unanticipated Agonist Properties:  Extending the Scope of Common Structure−Activity Relationships

Abstract

The synthesis, biological, and pharmacological evaluations of 14beta-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14beta-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (mu, kappa, delta), with the N-propyl derivative 19 displaying the highest affinity for the mu-receptor (K(i) = 0.09 nM).

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

“…Recently, we have reported that the introduction of a 14-phenylpropoxy group gives rise to extremely potent analgesics in morphinan-6-ones having a methyl, cyclopropylmethyl, or allyl group at the morphinan nitrogen. 10,16 Thus, it became apparent that 14-arylalkoxy substitution increases analgesic potency compared to 14-alkoxymorphinans such as 14-O-methyloxymorphone (1).…”

Synthesis and Pharmacological Activities of 6-Glycine Substituted 14-Phenylpropoxymorphinans, a Novel Class of Opioids with High Opioid Receptor Affinities and Antinociceptive Potencies

“…(19) Similar results were provided on differently N -substituted 14-phenylpropoxymorphinan-6-ones (e.g., N -allyl and N -cyclopropylmethyl substituted morphinans 5 and 6 ). (20) It was established that the presence of a 14-phenylpropoxy group increases both the agonist potency and the affinity for all three opioid receptor types while concurrently diminishing the selectivity for any of the receptors. The two classical opioid antagonists naloxone ( 7 ) and naltrexone ( 8 ) were converted into highly active analgesic agents by introducing a phenylpropoxy group in position 14 (compounds 5 and 6 , respectively).…”

“…The two classical opioid antagonists naloxone ( 7 ) and naltrexone ( 8 ) were converted into highly active analgesic agents by introducing a phenylpropoxy group in position 14 (compounds 5 and 6 , respectively). (20) Moreover, derivatives of the selective μ opioid receptor antagonist cyprodime having a phenylpropoxy group at C-14 have also acted as potent antinociceptives in different pain models in mice after subcutaneous (sc) administration. (21) Thus, the presence of this substituent directs to a profound alteration in the pharmacological profile of morphinan-6-ones.…”

Design, Synthesis, and Biological Evaluation of 14-Heteroaromatic-Substituted Naltrexone Derivatives: Pharmacological Profile Switch from Mu Opioid Receptor Selectivity to Mu/Kappa Opioid Receptor Dual Selectivity

“…Similar discrepant results have also been observed by other research groups. 50 We also noticed that the introduction of a substitution at the 14-position of morphinan skeleton could be crucial in altering the pharmacological profile 51 while the orientation (in the manner of rotation freedom) of such substitution at this position may lead to high potency MOR agonism activity during the development of some pseudo-irreversible opioid receptor antagonists. 52-54 In combination of our observation, a more vivid picture of 14-substitution impact on the pharmacology of morphinan skeleton derivatives is now available.…”