3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor

Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure–activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q2) regression value of 0.6, and a non-cross validated r2 of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r2 >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [3H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50 = 1.78 μM) and its phenethyl derivative (IC50 = 1.54 μM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ1) receptor.

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