CoMFA and CoMSIA Investigations Revealing Novel Insights into the Binding Modes of Dopamine D3 Receptor Agonists
Citations Over Time
Abstract
As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
Related Papers
- → Differential visualization of dopamine D2 and D3 receptors in rat brain(1993)23 cited
- → The dopamine D3 receptor and schizophrenia: pharmacological, anatomical and genetic approaches(1995)44 cited
- → Dopamine D2/D3 receptor agonists produce antidepressant‐like effects in the rat forced swim test through co‐activation of both receptor subtypes(2008)1 cited
- → DOPAMINE D1, D2, D3, D4 RECEPTOR GENE POLYMORPHISMS AND SCHIZOPHRENIA(1992)
- → Dopamine D2 receptor; dopamine D3 receptor(2012)