3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor
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Date
2013
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
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 (r1) 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 validatedr2 of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of atest set with an r2 >0.7. We also describe here the docking of the PCU-derivedcompounds into a homology model of the sigma-1 (r1) 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 anoxa-PCU, NGP1-01 (IC50 = 1.78 lM) and its phenethyl derivative (IC50 = 1.54 lM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(r1)
Description
Keywords
Pentacycloundecylamines, Sigma-1 receptor, CoMFA, Glaucomatous neurodegeneration, Homology modeling
Citation
Geldenhuys, W.J. et al. (2013). 3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor. Bioorganic & Medicinal Chemistry Letters, 23: 1707 – 1711