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.

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Greiner E, Spetea M, Krassnig R, Schullner F, Aceto M, Harris LS, Traynor JR, Woods JH, Coop A, Schmidhammer H

J Med Chem. 2003 Apr 24;46(9):1758-63.

PubMed ID

12699394 [ View in PubMed

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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).

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Morphine	Kappa-type opioid receptor	Ki (nM)	113	N/A	N/A	Details