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  • Title: Synthesis of 7,9-diazabicyclo[4.2.2]decanes as conformationally restricted κ receptor agonists: fine tuning of the dihedral angle of the ethylenediamine pharmacophore.
    Author: Sunnam SK, Rack E, Schepmann D, Wünsch B.
    Journal: Eur J Med Chem; 2011 Jun; 46(6):1972-82. PubMed ID: 21481987.
    Abstract:
    In order to slightly modify the orientation of the pharmacophoric structural elements of the potent κ agonists 7 and 8, the three-membered bridge of these compounds was enlarged to four carbon atoms. Reductive amination of the bicyclic ketone 11 with pyrrolidine and NaBH(OAc)3 provided the pyrrolidine 12 with excellent diastereoselectivity (>99:1). The diastereomeric pyrrolidine 24 was established by a stepwise strategy, involving an unselective nucleophilic substitution of the triflate 20 with NaN3 as key step. The synthesis of 9 and 10 was completed by LiAlH4 reduction, replacement of the PMB group at N-9 with a (3,4-dichlorophenyl)acetyl residue and the N-7-benzyl group with the methoxycarbonyl moiety. The κ receptor affinity of the new compounds is strongly dependent on the stereochemistry and the N-7-substituent. The (1RS,2SR,6SR)-configured pyrrolidine 9 with a methoxycarbonyl moiety at N-7 represents the most potent κ ligand (Ki=65 nM) of this series. The 65fold lower κ affinity of 9 compared with its smaller homologue 7 is partly explained by 9 being a racemic mixture, and the slightly modified dihedral angle of the pharmacophoric N(pyrrolidine)-C-C-N(dichlorophenylacetyl) substructure. However, the additional methylene moiety, which enlarges the size of the bridge, is assumed to be responsible for the reduced κ affinity.
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