Synthesis and Biological Evaluation of 14‐Alkoxymorphinans Part 4 opioid agonists and partial opioid agonists in a series of <i>N</i>‐(cyclobutylmethyl)‐14‐methoxymorphinan‐6‐ones

Schmidhammer, Helmut; Burkard, W. P.; Eggstein-Aeppli, Lislott

doi:10.1002/hlca.19890720607

Cited by 9 publications

(13 citation statements)

References 9 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected and in agreement with the previous determinations of the positive influence of 14-alkoxy substituents in morphinan-6-ones, 2,3,15 all of the tested 14-alkoxymorphinans, except 10, showed very high µ opioid receptor affinity, with K i values ranging between 0.12 and 0.61 nM (Table 1). Compounds 6-9 and 11 displayed a 10-to 54-fold enhanced affinity to the µ receptor in comparison to morphine, and comparable µ affinity to 14-O-methyloxymorphone (1) and 14-methoxymetopon (3).…”

Section: Resultssupporting

confidence: 92%

See 1 more Smart Citation

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-one derivatives were synthesized and biologically evaluated. Compounds 6-9 and 11 displayed affinities in the subnanomolar range to mu opioid receptors which were comparable to 14-O-methyloxymorphone (1) and 14-methoxymetopon (3), and higher than oxymorphone (2). Opioid binding affinity was sensitive to the character and length of the substituent in position 14. In smooth muscle preparations they behaved as potent agonists. Antinociceptive potencies of compounds 6-11 in the hot-plate test after sc administration in mice were considerably greater than the potency of morphine. In the colonic propulsion test, the most potent analgesic compound 7 showed negligible constipating activity at the analgesic dose. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. Introduction of a 5-methyl group has no significant effect on in vitro biological activities, but resulted in decreased antinociceptive potency.

show abstract

Section: Resultssupporting

confidence: 92%

“…3-Benzyloxy-14-(2′,6′-dichlorobenzyloxy)-4,5R-epoxy-17-methylmorphinan-6-spiro-2′-(1,3-dioxolane) (15). Compound 15 was prepared essentially by the procedure described for the synthesis of compound 14.…”

Section: -Allyloxy-45r-epoxy-3-hydroxy-17-methylmorphinan-6-one Hydro...mentioning

confidence: 99%

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…46−48 Substituents such as cyclopropylmethyl or allyl at the nitrogen have been commonly associated with an antagonist character in this series of opioids. On the other hand, there are a number of examples where substitution at C-14 affords potent analgesics independent of the substituent nature at the morphinan nitrogen.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2011

Self Cite

View full text Add to dashboard Cite

The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11−18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in δ and κ activities, hence resulting in a loss of μ receptor selectivity. All compounds (11−18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14-methoxy analogues 9 and 10, respectively. Even derivatives 15−18 with an N-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.

show abstract

“…Established and generally accepted structure−activity relationship (SAR) models have assigned critical importance in the development of opioid agonist/antagonist properties of morphinan-6-ones to the N -substituent. − Substituents such as cyclopropylmethyl (CPM) or allyl on the nitrogen have been commonly associated with an antagonist character in this series of opioids . While 14-methoxy- N -methylmorphinan-6-ones (Figure ) such as 14- O -methyloxymorphone , ( 1 ) and 14-methoxymetopon − ( 2 ) are known to act as agonists at the μ-opioid receptor, the replacement of the N -methyl group by an allyl or a CPM group typically results in a complete loss of agonist activity, thus leading to pure antagonists.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

Self Cite

View full text Add to dashboard Cite

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).

show abstract

Synthesis and Biological Evaluation of 14‐Alkoxymorphinans Part 4 opioid agonists and partial opioid agonists in a series of N‐(cyclobutylmethyl)‐14‐methoxymorphinan‐6‐ones

Cited by 9 publications

References 9 publications

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

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

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

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

Contact Info

Product

Resources

About