作者: Panasis, Diandra ; Saez, Julianna ; Alkhatib, Mohammad ; Brunt, Dylan ; Hemby, Scott E ; Pham, Mimi L ; Crowthers, Raymond ; Sibley, David R ; Nilson, Ashley N ; Akca, Ebrar ; Korankyi, Ivana V ; Newman, Amy Hauck ; Slusher, Barbara S ; Stewart, Kent D ; Wu, Chun ; Nguyen, Catherine ; Placide, Rebekah ; Rais, Rana ; DePierro, Jacquelyn ; Ladik, Maria ; Keck, Thomas M ; Shah, Nisha ; Jakobs, Franziska M ; McIntosh, Scot ; Muccilli, Abigail ; McBride, Connor ; Sanchez, Moises Ximello ; Kurtyan, Emily ; Boateng, Comfort A ; Boldizsar, Noelia ; Bonifazi, Alessandro ; Free, R Benjamin ; Kelshikar, Shreya ; Stallings, Leia S ; Maslonka, Brianna

Pharmacological targeting of the dopamine D₄ receptor (D₄R)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D₄R. We identified several compounds with high D₄R binding affinity (K_i ≤ 6.9 nM) and >91-fold selectivity over other D₂-like receptors (D₂R, D₃R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D₄R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUC_brain/plasma > 3). 16f (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D₄R-selective antagonists. Off-target antagonism of 5-HT_2A or 5-HT_2B may also contribute to these effects. Results with 16f support further efforts to target D₄R in SUD treatment.

2014-09-11·ACS Medicinal Chemistry Letters3区 · 医学

Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D₄ Receptor with in Vivo Activity

3区 · 医学

Article

作者: Bubser, Michael ; Hopkins, Corey R. ; Hayes, John P. ; Jones, Carrie K. ; Wepy, James A. ; Berry, Cynthia B. ; Daniels, J. Scott ; Locuson, Charles W. ; Lindsley, Craig W.

Herein, we report the structure-activity relationship of a chiral morpholine-based scaffold, which led to the identification of a potent and selective dopamine 4 (D4) receptor antagonist. The 4-chlorobenzyl moiety was identified, and the compound was designated an MLPCN probe molecule, ML398. ML398 is potent against the D4 receptor with IC50 = 130 nM and K i = 36 nM and shows no activity against the other dopamine receptors tested (>20 μM against D1, D2S, D2L, D3, and D5). Further in vivo studies showed that ML398 reversed cocaine-induced hyperlocomotion at 10 mg/kg.

100 项与 ML-398 相关的药物交易

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