title: CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Boeckler
authors.forename: Ursula
authors.initials: U
authors.lastname: Ohnmacht
authors.forename: Thomas
authors.initials: T
authors.lastname: Lehmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Utz
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002417:Cattle; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism; D050637:Receptors, Dopamine D3; D013237:Stereoisomerism
chemical_list: C493593:DRD3 protein, human; D007212:Indolizines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3