title: The discovery of indole full agonists of the neurotensin receptor 1 (NTSR1).
abstract: Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, such as schizophrenia, Parkinson's disease and drug addiction. The discovery of small-molecule non-peptide neurotensin receptor (NTSR) modulators would represent an important breakthrough as such compounds could be used as pharmacological tools, to further decipher the cellular functions of neurotensin, and potentially as therapeutic agents to treat human disease. Herein, we report the identification of non-peptide low-micromolar neurotensin receptor 1 (NTSR1) full agonists, discovered through structural optimization of the known NTSR1 partial agonist 1. In vitro cellular screenings, based on an intracellular Ca(2+) mobilization assay, revealed our best hit molecule 8 (SR-12062) to have an EC50 of 2 μM at NTSR1 with full agonist behaviour (Emax=100%), showing a higher efficacy and ∼90-fold potency improvement compared to parent compound 1 (EC50=178 μM; Emax=17%).
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Di Fruscia
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
authors.forename: Marcel
authors.initials: M
authors.lastname: Koenig
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
authors.forename: Sahba
authors.initials: S
authors.lastname: Tabrizifard
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: McDonald
authors.affiliation: Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA. Electronic address: kameneck@scripps.edu.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D018028:Receptors, Neurotensin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor
keywords: Indole agonists; Neurotensin; Neurotensin agonists; Neurotensin receptors; SR-12062