Conformationally Restricted σ1 Receptor Antagonists from (−)-Isopulegol

Antagonists at σ₁ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (1), aminodiols 8-11 were obtained and transformed into bicyclic 13-16 and tricyclic ligands 19-22. Aminodiols 8-11 showed higher σ₁ affinity than the corresponding bicyclic 13-16 and tricyclic derivatives 19-22. (R)-configuration in the side chain of aminodiols (8 and 10) led to higher σ₁ affinity than (S)-configuration (9 and 11). 4-Benzylpiperidines (b-series) revealed higher σ₁ affinity than 4-phenylbutylamines (a-series). Aminodiol 8b showed very high σ₁ affinity (K_i = 1.2 nM), excellent selectivity over σ₂ receptors, and promising logD_7.4 (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the σ₁ affinity and selectivity on an atomistic level. In the capsaicin assay, 8b exhibited similar antiallodynic activity to the prototypical σ₁ antagonist S1RA. The antiallodynic activity of 8b was removed by co-application of the σ₁ agonist PRE-084, proving σ₁ antagonism being involved in the antiallodynic effect.