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Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80
Author(s) -
Jung Bettina,
Englberger Werner,
Wünsch Bernhard
Publication year - 2005
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200400994
Subject(s) - chemistry , bicyclic molecule , stereochemistry , ketone , μ opioid receptor , moiety , stereoselectivity , enantiomer , chemical synthesis , agonist , receptor , organic chemistry , in vitro , biochemistry , catalysis
In order to find novel δ opioid receptor agonists, the pharmacophoric benzhydryl moiety of the lead compound SNC 80 ( 1 ) was dissected and the phenyl residues were attached to different positions of the 6,8‐diazabicyclo[3.2.2]nonane core system ( 4 ). The position of the carboxamido group, the stereochemistry, the C3/C4 bond order and the kind and length of the spacer X were considered. The resulting compounds were compared with the four energetically most favourable conformations of SNC 80 by a multifit analysis. These calculations led to the structures 5 ‐ 10 , which fit best to SNC 80. Herein the synthesis of one of these compounds ( 9 ) is described. Starting from (S)‐glutamate two alternative routes are detailed to obtain the key intermediate 14 . A variation of the Dieckmann cyclization, which uses trapping of the first cyclization product with ClSiMe 3 provided the mixed acetal 20 , which was carefully hydrolyzed to yield the bicyclic ketone 17 . Stereoselective addition of phenylmagnesium bromide, dehydration, LiAlH 4 reduction and exchange of the N‐6 residue afforded the designed compound 9 . The affinities of 9 towards δ, μ, κ and ORL1 receptors were determined in receptor binding studies with radioligands. Only moderate receptor affinity was found.