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

Abstract

To discover novel delta-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 delta, mu, and kappa receptors, as well as sigma 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 delta 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 delta ligands the complete benzhydryl moiety was introduced into the bicyclic scaffold. The determined delta receptor affinities show that compounds based on an (R)-glutamate-derived bicyclic scaffold possess higher delta receptor affinity than their (S)-glutamate-derived counterparts. Furthermore, an intact benzhydryl moiety leads to delta 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 delta receptor affinity of this series: K(i)=24 nM. Whereas the highly potent delta ligands reveal good selectivity against mu and kappa receptors, the sigma(1) and/or sigma(2) affinities of some compounds are almost in the same range as their delta receptor affinities, such as compound 25 (sigma(2): K(i)=83 nM; delta: K(i)=75 nM). In [(35)S]GTPgammaS assays the most potent delta 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.