ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Barak, LS; Bai, Y; Peterson, S; Evron, T; Urs, NM; Peddibhotla, S; Hedrick, MP; Hershberger, P; Maloney, PR; Chung, TDY; Rodriguiz, RM; Wetsel, WC; Thomas, JB; Hanson, GR; Pinkerton, AB; Caron, MG

Published Date

  • July 15, 2016

Published In

Volume / Issue

  • 11 / 7

Start / End Page

  • 1880 - 1890

PubMed ID

  • 27119457

Pubmed Central ID

  • 27119457

Electronic International Standard Serial Number (EISSN)

  • 1554-8937

Digital Object Identifier (DOI)

  • 10.1021/acschembio.6b00291

Language

  • eng

Conference Location

  • United States