Conformationally constrained ethylenediamines: synthesis and receptor binding of 6,8-Diazabicyclo[3.2.2]nonanes Original Research Article

The synthesis and receptor affinity of 6,8-diazabicyclo[3.2.2]nonanes representing conformationally constrained ethylenediamines are described. The Dieckmann analogous cyclization of the (piperazin-2-yl)propionate 9 provided the bicyclononane 10 only, when the first cyclization product was trapped with chlorotrimethylsilane. 10 was stereoselectively transformed into the bicyclic amines 19a,b and amides 22a,b, which were investigated in competition experiments with radioligands for their σ1-, σ2-, κ-, and μ-receptor affinities. The (2R)-configured dimethylamine 19a showed promising σ1-receptor affinity (Ki=23.8 nM) and selectivity, whereas the (2S)-configured (dichlorophenyl)acetamide 22b displayed a σ-receptor binding profile (σ1: Ki=184 nM; σ2: Ki=263 nM) very similar to the binding profile of the atypical antipsychotic BMY-14802 (26).