9 research outputs found
Discovery of [11C]MK-6884: a positron emission tomography (PET) imaging agent for the study of M4 muscarinic receptor positive allosteric modulators (PAMs) in neurodegenerative diseases
The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884
The Neuronal Nitric Oxide Synthase Inhibitor 7-Nitroindazole Also Inhibits the Monoamine Oxidase-B-Catalyzed Oxidation of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Reappearance of Hippocampal CA1 Neurons after Ischemia is Associated with Recovery of Learning and Memory
Novel Bioactivation Mechanism of Reactive Metabolite Formation from Phenyl Methyl-Isoxazoles
Effect of Solvents on the Time-Dependent Inhibition of CYP3A4 and the Biotransformation of AZD3839 in Human Liver Microsomes and Hepatocytes
Optimization of human dose prediction by using quantitative and translational pharmacology in drug discovery
Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase
3‑Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na<sub>V</sub>1.7 with Efficacy in Rat Pain Models
The voltage-gated sodium channel Na<sub>V</sub>1.7 is
believed
to be a critical mediator of pain sensation based on clinical genetic
studies and pharmacological results. Clinical utility of nonselective
sodium channel blockers is limited due to serious adverse drug effects.
Here, we present the optimization, structure–activity relationships,
and in vitro and in vivo characterization of a novel series of Na<sub>V</sub>1.7 inhibitors based on the oxoisoindoline core. Extensive
studies with focus on optimization of Na<sub>V</sub>1.7 potency, selectivity
over Na<sub>V</sub>1.5, and metabolic stability properties produced
several interesting oxoisoindoline carboxamides (<b>16A</b>, <b>26B</b>, <b>28</b>, <b>51</b>, <b>60</b>, and <b>62</b>) that were further characterized. The oxoisoindoline carboxamides
interacted with the local anesthetics binding site. In spite of this,
several compounds showed functional selectivity versus Na<sub>V</sub>1.5 of more than 100-fold. This appeared to be a combination of subtype
and state-dependent selectivity. Compound <b>28</b> showed concentration-dependent
inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation
from SNL rats. Compounds <b>16A</b> and <b>26B</b> demonstrated
concentration-dependent efficacy in preclinical behavioral pain models.
The oxoisoindoline carboxamides series described here may be valuable
for further investigations for pain therapeutics