ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse

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• 作者：Larry S. Barak ; Yushi Bai ; Sean Peterson ; Tama Evron ; Nikhil M. Urs ; Satyamaheshwar Peddibhotla ; Michael P. Hedrick ; Paul Hershberger ; Patrick R. Maloney ; Thomas D.Y. Chung ; Ramona M. Rodriguiz ; William C. Wetsel ; James B. Thomas ; Glen R. Hanson ; Anthony B. Pinkerton ; Marc G. Caron
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：July 15, 2016
• 年：2016
• 卷：11
• 期：7
• 页码：1880-1890
• 全文大小：778K
• 年卷期：0
• ISSN：1554-8937

文摘

Pharmacological treatment for methamphetamine addiction will provide important societal benefits. Neurotensin receptor NTR1 and dopamine receptor distributions coincide in brain areas regulating methamphetamine-associated reward, and neurotensin peptides produce behaviors opposing psychostimulants. Therefore, undesirable methamphetamine-associated activities should be treatable with druggable NTR1 agonists, but no such FDA-approved therapeutics exist. We address this limitation with proof-of-concept data for ML314, a small-molecule, brain penetrant, β-arrestin biased, NTR1 agonist. ML314 attenuates amphetamine-like hyperlocomotion in dopamine transporter knockout mice, and in C57BL/6J mice it attenuates methamphetamine-induced hyperlocomotion, potentiates the psychostimulant inhibitory effects of a ghrelin antagonist, and reduces methamphetamine-associated conditioned place preference. In rats, ML314 blocks methamphetamine self-administration. ML314 acts as an allosteric enhancer of endogenous neurotensin, unmasking stoichiometric numbers of hidden NTR1 binding sites in transfected-cell membranes or mouse striatal membranes, while additionally supporting NTR1 endocytosis in cells in the absence of NT peptide. These results indicate ML314 is a viable, preclinical lead for methamphetamine abuse treatment and support an allosteric model of G protein-coupled receptor signaling.