Development of molecular tools based on the dopamine D 3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 13; p. 3491
• Main Authors: Stößel, Anne, Brox, Regine, Purkayastha, Nirupam, Hübner, Harald, Hocke, Carsten, Prante, Olaf, Gmeiner, Peter
• Format: Journal Article
• Language: English
• Published: England 01-07-2017
• Subjects: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Ligands; Mice; Molecular Structure; Positron-Emission Tomography; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rats; Receptors, Dopamine D3 - antagonists & inhibitors; Receptors, Dopamine D3 - metabolism; Structure-Activity Relationship; Autoradiography; Self-administration; Positron emission tomography (PET); Food maintained behavior; Selective D antagonist; Drug maintained behavior; Fluorine-18; Dopamine D receptor; Subtype selectivity
• ISSN: 1464-3391
• DOI: 10.1016/j.bmc.2017.04.036

Dopamine D
receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D
a highly promising biological target. The previously described dopamine D
receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [
F]2, a [
F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D
-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.