528854-53-7Relevant articles and documents
Synthesis and biological evaluation of 14-alkoxymorphinans 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the μ opioid receptor antagonist cyprodime
Spetea, Mariana,Schüllner, Falko,Moisa, Radu C.,Berzetei-Gurske, Ilona P.,Schraml, Barbara,D?rfler, Cynthia,Aceto, Mario D.,Harris, Louis S.,Coop, Andrew,Schmidhammer, Helmut
, p. 3242 - 3247 (2007/10/03)
The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at μ, δ, and κ opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the μ opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase μ affinity in the case of benzyloxy, while a phenylpropoxy group reduces μ affinity. The δ and κ affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the μ opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at δ and κ receptors were also observed. 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. In the [ 35S]GTPγS binding assay, all tested compounds were partial agonists at μ and δ receptors. Compounds 8 and 17 showed antagonism at κ receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.
Synthesis and biological evaluation of 14-alkoxymorphinans. 18.1 N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: Extending the scope of common structure-activity relationships
Greiner, Elisabeth,Spetea, Mariana,Krassnig, Roland,Schüllner, Falko,Aceto, Mario,Harris, Louis S.,Traynor, John R.,Woods, James H.,Coop, Andrew,Schmidhammer, Helmut
, p. 1758 - 1763 (2007/10/03)
The synthesis, biological, and pharmacological evaluations of 14β-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 14β-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 (μ, κ, δ), with the N-propyl derivative 19 displaying the highest affinity for the μ-receptor (Ki = 0.09 nM).
