Conformationally Restricted σ Receptor Antagonists from (-)-Isopulegol.

Antagonists at σ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (), aminodiols were obtained and transformed into bicyclic and tricyclic ligands . Aminodiols showed higher σ affinity than the corresponding bicyclic and tricyclic derivatives . ()-configuration in the side chain of aminodiols ( and ) led to higher σ affinity than ()-configuration ( and ). 4-Benzylpiperidines (-series) revealed higher σ affinity than 4-phenylbutylamines (-series). Aminodiol showed very high σ affinity ( = 1.2 nM), excellent selectivity over σ receptors, and promising log (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the σ affinity and selectivity on an atomistic level. In the capsaicin assay, exhibited similar antiallodynic activity to the prototypical σ antagonist S1RA. The antiallodynic activity of was removed by co-application of the σ agonist PRE-084, proving σ antagonism being involved in the antiallodynic effect.