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Issue 12, 2016
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Synthesis and pharmacological evaluation of conformationally restricted κ-opioid receptor agonists

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Abstract

In order to obtain novel polar κ agonists the κ-pharmacophoric ethylenediamine structural element was embedded in a rigid bicyclic scaffold. The pyridooxazine system was selected since it contains polar O- and N-atoms in the 1- and 7-positions, respectively. An axially oriented pyrrolidine ring was attached at the 5-position and the dichlorophenylacetyl moiety was introduced at N-4. The key steps of the 11-step synthesis are a double Henry reaction of iminodiacetaldehyde 7 with nitromethane and the introduction of the azido moiety of 13 by Mitsunobu reaction of the alcohol 11 with Zn(N3)2·(pyridine)2. The X-ray crystal structure analysis of 17b shows a dihedral angle N(acyl)-C-C-N(pyrrolidine) of −60.8(2)°, which is close to the postulated optimal angle. Moderate κ affinity was found for the secondary amine 17a (Ki = 132 nM) and the methyl derivative 17b (Ki = 266 nM). In the [35S]GTPγS assay the secondary amine 17a showed 28% agonistic activity compared to U-69,593. Although 17a and 17b contain all crucial κ-pharmacophoric elements, their κ affinity is rather low, which might be attributed to the unfavorable cis-orientation of the pyrrolidine ring and the dichlorophenylacetamido moiety and/or the additional O- and N-atoms in the 1- and 7-positions.

Graphical abstract: Synthesis and pharmacological evaluation of conformationally restricted κ-opioid receptor agonists

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Publication details

The article was received on 01 Aug 2016, accepted on 21 Sep 2016 and first published on 23 Sep 2016


Article type: Research Article
DOI: 10.1039/C6MD00441E
Citation: Med. Chem. Commun., 2016,7, 2368-2380
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    Synthesis and pharmacological evaluation of conformationally restricted κ-opioid receptor agonists

    Y. Wenker, M. Soeberdt, C. Daniliuc, S. Ständer, D. Schepmann and B. Wünsch, Med. Chem. Commun., 2016, 7, 2368
    DOI: 10.1039/C6MD00441E

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