Molecular modeling directed synthesis of a bicyclic analogue of the delta opioid receptor agonist SNC 80.
In order to find novel delta 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 delta, mu, kappa and ORL1 receptors were determined in receptor binding studies with radioligands. Only moderate receptor affinity was found.
Jung
Bettina
B
Institut für Pharmazeutische und Medizinische Chemie, Münster, Germany.
Englberger
Werner
W
Wünsch
Bernhard
B
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D016466:CHO Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006224:Cricetinae; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013329:Structure-Activity Relationship
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide