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.
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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sunnam
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rack
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D053961:Azabicyclo Compounds; D005029:Ethylenediamines; D008024:Ligands; D017473:Receptors, Opioid, kappa; C031234:ethylenediamine