title: CoMFA and CoMSIA investigations of dopamine D3 receptor ligands leading to the prediction, synthesis, and evaluation of rigidized FAUC 365 analogues.
abstract: Taking advantage of our in-house experimental data on dopamine D3 receptor modulators, we have successfully established highly significant CoMFA and CoMSIA models (q(cv)2 = 0.82/0.76). These models were carefully investigated to assure their stability and predictivity (r(pred)2 = 0.65/0.61) and subsequently applied to guide experimental investigations on the synthesis and receptor binding of three conformationally restricted D3 ligands. Besides the high D3 affinity, the test compound 45, incorporating a trans-1,4-cyclohexylene partial structure, exhibited improved (approximately 3200-fold) selectivity over the D4 subtype.
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Ismail
authors.initials: I
authors.lastname: Salama
authors.forename: Karin
authors.initials: K
authors.lastname: Schlotter
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
authors.forename: Frank
authors.initials: F
authors.lastname: Boeckler
mesh_terms: D020650:Combinatorial Chemistry Techniques; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C467223:FAUC 365; D008024:Ligands; D010879:Piperazines; D050637:Receptors, Dopamine D3; D013876:Thiophenes; C120565:BP 897