ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse.
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.
Duke University Medical Center , Durham, North Carolina 27710, United States.
Larry S
LS
Barak
Duke University Medical Center , Durham, North Carolina 27710, United States.
Yushi
Y
Bai
Duke University Medical Center , Durham, North Carolina 27710, United States.
Sean
S
Peterson
Duke University Medical Center , Durham, North Carolina 27710, United States.
Tama
T
Evron
Duke University Medical Center , Durham, North Carolina 27710, United States.
Nikhil M
NM
Urs
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , Orlando, Florida 32827, United States.
Satyamaheshwar
S
Peddibhotla
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , La Jolla, California 92037, United States.
Michael P
MP
Hedrick
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , Orlando, Florida 32827, United States.
Paul
P
Hershberger
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , Orlando, Florida 32827, United States.
Patrick R
PR
Maloney
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , La Jolla, California 92037, United States.
Thomas D Y
TD
Chung
Duke University Medical Center , Durham, North Carolina 27710, United States.
Ramona M
RM
Rodriguiz
Duke University Medical Center , Durham, North Carolina 27710, United States.
William C
WC
Wetsel
RTI International , 3040 E Cornwallis Road, Durham, North Carolina 27709, United States.
James B
JB
Thomas
Department of Pharmacology and Toxicology, University of Utah , 260 S. Campus Drive, Salt Lake City, Utah 84112, United States.
Glen R
GR
Hanson
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute , La Jolla, California 92037, United States.
Anthony B
AB
Pinkerton
Duke University Medical Center , Durham, North Carolina 27710, United States.
Marc G
MG
Caron
D000494:Allosteric Regulation; D019969:Amphetamine-Related Disorders / Q000378:metabolism*; D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D008024:Ligands; D008124:Locomotion / Q000187:drug effects; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; C000621047:ML314 compound; D010879:Piperazines; D011799:Quinazolines; D018028:Receptors, Neurotensin; D008694:Methamphetamine