Conformationally-flexible benzamide analogues as dopamine D₃ and σ₂ receptor ligands

A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine (D₂, D₃ and D ₄) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (K_i value=2 nM) and moderate selectivity (30-fold) for D₃ compared to D₂ receptors. In addition, this series of compounds were also tested for affinity at σ ₁ and σ₂ receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D _2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for σ₂ versus σ₁ receptors. Consequently, these novel compounds may be useful for characterizing the functional role of σ₂ receptors and for imaging the σ₂ receptor status of tumors in vivo with PET.