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ACS Chem Biol. 2016 Jul 15;11(7):1880-90. doi: 10.1021/acschembio.6b00291. Epub 2016 May 5.

ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse.

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Duke University Medical Center , Durham, North Carolina 27710, United States.
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , Orlando, Florida 32827, United States.
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , La Jolla, California 92037, United States.
RTI International , 3040 E Cornwallis Road, Durham, North Carolina 27709, United States.
Department of Pharmacology and Toxicology, University of Utah , 260 S. Campus Drive, Salt Lake City, Utah 84112, United States.


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.

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