Conformationally Restricted?1 Receptor Antagonists from (-)-Isopulegol

Antagonists at sigma 1 receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (1), aminodiols 8-11 were obtained and trans-formed into bicyclic 13-16 and tricyclic ligands 19-22. Amino-diols 8-11 showed higher sigma 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 sigma 1 affinity than (S)-configuration (9 and 11). 4-Benzylpiperidines (b-series) revealed higher sigma 1 affinity than 4-phenylbutylamines (a-series). Aminodiol 8b showed very high sigma 1 affinity (Ki = 1.2 nM), excellent selectivity over sigma 2 receptors, and promising logD7.4 (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the sigma 1 affinity and selectivity on an atomistic level. In the capsaicin assay, 8b exhibited similar antiallodynic activity to the prototypical sigma 1 antagonist S1RA. The antiallodynic activity of 8b was removed by co-application of the sigma 1 agonist PRE-084, proving sigma 1 antagonism being involved in the antiallodynic effect.