Synthesis and pharmacological evaluation of bicyclic SNC80 analogues with separated benzhydryl moiety

Directed by molecular modeling studies the pharmacophoric benzhydryl moiety of the δ 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 δ 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 δ 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 RhCl3, 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 [3H]-deltorphine II only ent-3 showed considerable δ receptor affinity (Ki = 740 nM). Since ent-3 also interacts with μ receptors (Ki = 250 nM) it belongs to the very interesting compound class of mixed δ/μ ligands.

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