title: 3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor.
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 (σ1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q(2)) regression value of 0.6, and a non-cross validated r(2) of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r(2) >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 [(3)H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50=1.78μM) and its phenethyl derivative (IC50=1.54μM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ1) receptor.
authors: Department of Pharmaceutical Sciences, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA. wgeldenh@neomed.edu
authors: Werner J
authors: WJ
authors: Geldenhuys
authors: Nicholas
authors: N
authors: Novotny
authors: Sarel F
authors: SF
authors: Malan
authors: Cornelis J
authors: CJ
authors: Van der Schyf
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism; D001372:Aza Compounds / Q000737:chemistry; D001665:Binding Sites; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D017480:Receptors, sigma / Q000737:chemistry* / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000588:Amines; D001372:Aza Compounds; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor