ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse.
ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse.
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DOI：
10.1021/acschembio.6b00291
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发表时间：
2016-07-15
影响因子：
4
通讯作者：
Caron MG
中科院分区：
文献类型：
--
作者：
Barak LS;Bai Y;Peterson S;Evron T;Urs NM;Peddibhotla S;Hedrick MP;Hershberger P;Maloney PR;Chung TD;Rodriguiz RM;Wetsel WC;Thomas JB;Hanson GR;Pinkerton AB;Caron MG
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 wild type 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.
