A systematic exploration of the effects of flexibility and basicity on sigma (σ) receptor binding in a series of substituted diamines

Abstract

The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.

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“…This approach has been successful and led to the discovery of several high affinity ligands. 82 , 85 , 89 Moreover, some of the reported pharmacophore models addressed the σR subtype selectivity and highlighted the feature required for binding at each subtype. However, to date, we believe that selectivity against other CNS receptors has not been adequately addressed using ligand-based design methods.…”

“…Generally speaking, the development of σ 1 R ligands depended mainly on ligand-based design, especially on the general pharmacophoric features suggested by Glennon and co-workers. , Despite the availability of the σ 1 R crystal structure since 2016, several studies still depend on the general sigma pharmacophore for the design of novel ligands. This approach has been successful and led to the discovery of several high affinity ligands. ,, Moreover, some of the reported pharmacophore models addressed the σR subtype selectivity and highlighted the feature required for binding at each subtype. However, to date, we believe that selectivity against other CNS receptors has not been adequately addressed using ligand-based design methods.…”