Fancy bioisosteres: synthesis, SAR, and pharmacological investigations of novel nonaromatic dopamine D3 receptor ligands.
Structural variations of the lead compound FAUC 88 led to dopaminergic enynes with an extended pi-system when Pd-catalyzed cross coupling reactions were employed for the key reaction steps. The dienyne 9b displayed substantial affinity for the dopamine receptor subtype D3 and remarkable selectivity over D4. Compared to FAUC 88, the novel fancy bioisostere 9b displayed reduced ligand efficacy. DFT-based conformational analysis of the test compound 9b, including the calculation of diagnostic magnetic shielding properties and their comparison with experimentally derived NMR data, indicated a clear energetic preference for the s-trans geometry of the diene substructure.
Lenz
Carola
C
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Boeckler
Frank
F
Hübner
Harald
H
Gmeiner
Peter
P
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013552:Swine
D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3