Medicinal Chemistry of σ₁ Receptor Ligands: Pharmacophore Models, Synthesis, Structure Affinity Relationships, and...

In the first part of this chapter, we summarize the various pharmacophore models for σ₁ receptor ligands. Common to all of them is a basic amine flanked by two hydrophobic regions, representing the pharmacophoric elements. The development of computer-based models like the 3D homology model is described as well as the first crystal structure of the σ₁ receptor. The second part focuses on the synthesis and biological properties of different σ₁ receptor ligands, identified as 1-9. Monocyclic piperazines 1 and bicyclic piperazines 2 and 3 were developed as cytotoxic compounds, thus the IC₅₀ values of cell growth and survival inhibition studies are given for all derivatives. The mechanism of cell survival inhibition, induction of time-dependent apoptosis, of compound ent-2a is discussed. Experimentally determined σ₁ affinity shows good correlation with the results from molecular dynamics simulations based on a 3D homology model. Spirocyclic compounds 4 and 5 represent well-established σ₁ receptor ligands. The homologous fluoroalkyl derivatives 4 have favorable pharmacological properties for use as fluorinated PET tracers. The (S)-configured fluoroethyl substituted compound (S)-4b is under investigation as PET tracer for imaging of σ₁ receptors in the brain of patients affected by major depression. 1,3-Dioxanes 6c and 6d display a very potent σ₁ antagonist profile and the racemic 1,3-dioxane 6c has high anti-allodynic activity at low doses. The arylpropenylamines 7 are very potent σ₁ receptor ligands with high σ₁/σ₂ selectivity. The top compound 7g acts as an agonist as defined by its ability to potentiate neurite outgrowth at low concentrations. Among the morpholinoethoxypyrazoles 8, 8c (known as S1RA) reveals the most promising pharmacokinetic and physicochemical properties. Due to its good safety profile, 8c is currently being investigated in a phase II clinical trial for the treatment of neuropathic pain. The most potent ligand 9e of 3,4-dihydro-2(1H)-quinolones 9 shows promising anti-nociceptive activity in the formalin test.