Conformationally Restricted σ 1 Receptor Antagonists from (-)-Isopulegol.

Antagonists at σ 1 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 σ 1 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 σ 1 affinity than ( S )-configuration ( 9 and 11 ). 4-Benzylpiperidines ( b -series) revealed higher σ 1 affinity than 4-phenylbutylamines ( a -series). Aminodiol 8b showed very high σ 1 affinity ( K i = 1.2 nM), excellent selectivity over σ 2 receptors, and promising log D 7.4 (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the σ 1 affinity and selectivity on an atomistic level. In the capsaicin assay, 8b exhibited similar antiallodynic activity to the prototypical σ 1 antagonist S1RA. The antiallodynic activity of 8b was removed by co-application of the σ 1 agonist PRE-084, proving σ 1 antagonism being involved in the antiallodynic effect.