CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists

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 D3 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 D3 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.