Synthesis and pharmacological evaluation of bicyclic SNC80 analogues with separated benzhydryl moiety.
Directed by molecular modeling studies the pharmacophoric benzhydryl moiety of the delta opioid receptor agonist SNC80 was separated and the two phenyl residues were attached to different positions of the conformationally constrained 6,8-diazabicyclo[3.2.2]nonane framework in order to find novel delta agonists. The crucial reaction step in the chiral pool synthesis was the establishment of the three carbon bridge by a Dieckmann analogous cyclization of the allyl and propyl derivatives 6 and 7 to yield the mixed methyl silyl acetals 8 and 9, respectively. Stereoselective Grignard reaction, dehydration, and introduction of the pharmacophoric (N,N-diethylcarbamoylbenzyl) residue led to the designed delta receptor agonists 3, ent-3, and 20 with a double bond in the bicyclic framework. Hydrogenation of the allyl derivative 14 was performed with ammonium formate and Pd/C to yield the saturated ligands 24a and 24b. Removal of the allyl substituent with RhCl(3), hydrogenation of the ring system, and re-attachment of the allyl moiety provided the allyl derivatives 4a and 4b. In receptor binding studies with the radioligand [(3)H]-deltorphine II only ent-3 showed considerable delta receptor affinity (K(i)=740 nM). Since ent-3 also interacts with mu receptors (K(i)=250 nM) it belongs to the very interesting compound class of mixed delta/mu ligands.
Jung
Bettina
B
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, D-48149 Münster, Germany.
Englberger
Werner
W
Fröhlich
Roland
R
Schepmann
Dirk
D
Lehmkuhl
Kirstin
K
Wünsch
Bernhard
B
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001559:Benzhydryl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship
D001549:Benzamides; D001559:Benzhydryl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide