Sigma receptor ligands: a systematic approach in the design and synthesis

The sigma (σ) receptor is a neuromodulatory protein, widely expressed in the central nervous system (CNS) and to a lesser extent, the peripheral nervous system (PNS). Currently, two sigma receptor subtypes are known; sigma-1 receptors (S1R) and sigma-2-receptors (S2R), differing in molecular weight, pharmacological profile, distribution and function. The S1R has been implicated in depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease, drug abuse and more recently for its involvement in analgesia. The design of highly subtype-selective ligands is limited by a lack of information regarding the S1R/S2R binding site, a lack of crystal structure data on S1R until 2016, as well as a large structurally-diverse collection of known ligands. The currently accepted pharmacophore arising from this extensive ligand library proposes an alkylamine core tethered by two hydrophobic groups. Several highly subtype-selective S1R ligands fitting this pharmacophore have been previously synthesised in the Kassiou laboratory. This project investigates the optimisation of the lead 1-(benzofuran-2-ylmethyl)-4-(4-methoxybenzyl)piperazine with considerable focus on the flexibility and basicity of the piperazine core. Furthermore, bioisosteres of piperazine, phenyl, and the size tolerance of the hydrophobic sites of the S1R are also investigated. Binding affinities and sub-type selectivities were determined by in vitro binding assays of both S1R and S2R, with structure-activity relationships drawn from these modifications. This work aims at refining the S1R pharmacophore and to create S1R-selective ligands that can be used as probes to further understand the physiological role, as well as the morphology, of the S1R receptor. Ultimately, they may lead to remedies to treat the CNS diseases associated with this receptor