Synthesis and Pharmacological Evaluation of SNC80 Analogues with a Bridged Piperazine Ring

To discover novel δ‐opioid receptor ligands derived from SNC80 (1), a series of 6,8‐diazabicyclo[3.2.2]nonane derivatives bearing two aromatic moieties was prepared, and the affinity toward δ, μ, and κ receptors, as well as σ receptors, was investigated. After removal of the 4‐methoxybenzyl and 2,4‐dimethoxybenzyl protecting groups, the pharmacophoric N,N‐diethylcarbamoylbenzyl residue was attached to the 6,8‐diazabicyclo[3.2.2]nonane framework to yield the designed δ receptor ligands. In a first series of compounds the benzhydryl moiety of SNC80 was dissected, and one phenyl ring was attached to the bicyclic framework. In a second series of δ ligands the complete benzhydryl moiety was introduced into the bicyclic scaffold. The determined δ receptor affinities show that compounds based on an (R)‐glutamate‐derived bicyclic scaffold possess higher δ receptor affinity than their (S)‐glutamate‐derived counterparts. Furthermore, an intact benzhydryl moiety leads to δ receptor ligands that are more potent than compounds with two separated aromatic moieties. Compound 24, with the same spatial arrangement of substituents around the benzhydryl stereocenter as SNC80, shows the highest δ receptor affinity of this series: Ki=24 nM. Whereas the highly potent δ ligands reveal good selectivity against μ and κ receptors, the σ1 and/or σ2 affinities of some compounds are almost in the same range as their δ receptor affinities, such as compound 25 (σ2: Ki=83 nM; δ: Ki=75 nM). In [35S]GTPγS assays the most potent δ ligands 24 and 25 showed almost the same intrinsic activity as the full agonist SNC80, proving the agonistic activity of 24 and 25. The enantiomeric 4‐benzylidene derivatives 15 and ent‐15 showed selective cytotoxicity toward the 5637 (bladder) and A‐427 (small‐cell lung) human tumor cell lines. δ‐Opioid receptor agonists with a bridged piperazine scaffold were designed and synthesized. Whereas compounds with phenyl residues attached to different ring positions (compounds at center) did not show high δ affinity, introduction of the intact benzhydryl moiety at N8 (compounds at right) led to a potent δ agonist (Y=H2, Ki=24 nM).