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Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Sep 12; Vol. 62 (17), pp. 8357-8363. Date of Electronic Publication: 2019 Aug 20. - Publication Year :
- 2019
-
Abstract
- Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.
- Subjects :
- Administration, Oral
Allosteric Regulation drug effects
Animals
Biological Availability
Central Nervous System Diseases metabolism
Dopamine Plasma Membrane Transport Proteins deficiency
Dopamine Plasma Membrane Transport Proteins metabolism
Dose-Response Relationship, Drug
Female
Locomotion drug effects
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Structure
Quinazolines administration & dosage
Quinazolines chemistry
Rats
Receptors, Neurotensin metabolism
Structure-Activity Relationship
beta-Arrestins administration & dosage
beta-Arrestins chemistry
Central Nervous System Diseases drug therapy
Drug Discovery
Quinazolines pharmacology
Receptors, Neurotensin antagonists & inhibitors
beta-Arrestins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31390201
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b00340