CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Article Details
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Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hubner H, Gmeiner P
CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
J Med Chem. 2005 Apr 7;48(7):2493-508.
- PubMed ID
- 15801839 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Pramipexole Dopamine D2 receptor Ki (nM) 6300 N/A N/A Details Pramipexole Dopamine D2 receptor Ki (nM) 21 N/A N/A Details Pramipexole Dopamine D2 receptor Ki (nM) 1900 N/A N/A Details Pramipexole Dopamine D3 receptor EC 50 (nM) 1.5 N/A N/A Details Pramipexole Dopamine D3 receptor Ki (nM) 38 N/A N/A Details Pramipexole Dopamine D3 receptor Ki (nM) 0.88 N/A N/A Details Pramipexole Dopamine D4 receptor EC 50 (nM) 15 N/A N/A Details Pramipexole Dopamine D4 receptor Ki (nM) 8.1 N/A N/A Details Pramipexole Dopamine D4 receptor Ki (nM) 130 N/A N/A Details