Analogues of the decahydrobenzoquinolin-5-one class of sigma (σ) receptor ligands were used to probe the structure-activity relationship trends for this recently discovered series of σ ligands. In all, 29 representatives were tested for σ and opioid receptor affinity, leading to the identification of compounds possessing improved σ1 selectivity and, for the first time in this series, examples possessing preferential σ2 affinity. Several structural features associated with these selectivity trends have been identified. Two analogues of improved selectivity were evaluated in a binding panel of 43 CNS-relevant targets to confirm their sigma receptor preference.
Keywords: Biology-oriented synthesis; CNS; Decahydroquinoline; Radioligand binding; Sigma receptor; Structure-affinity relationship.
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