Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140).

@article{Guerrero2019DesignAS,
  title={Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140).},
  author={Miguel Guerrero and Mariangela Urbano and Eun-Kyong Kim and Ana M. Gamo and Sean Riley and Lusine Abgaryan and Nora B. Leaf and Lori Jean Van Orden and Steven J Brown and Jennifer Xie and Frank Porreca and Michael D Cameron and Hugh Rosen and Edward Roberts},
  journal={Journal of medicinal chemistry},
  year={2019},
  volume={62 4},
  pages={
          1761-1780
        }
}
κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety, and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)- N… 
In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist
TLDR
An in vitro, in vivo and in silico characterization of Compound A is presented by revealing this ligand as a KOR antagonist in vitro and in vivo, and this new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics.
Rational Design, Chemical Syntheses, and Biological Evaluations of Peripherally Selective Mu Opioid Receptor Ligands as Potential Opioid Induced Constipation Treatment.
TLDR
Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays, and seemed a promising agent to be further developed as an oral treatment for OIC.
Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders.
TLDR
While animal studies have indicated that compounds of this structural class are capable of normalizing withdrawal signs in animal models of cocaine and alcohol dependence and reducing cocaine andalcohol intake/seeking, additional studies are needed to determine the value of these second generation KOR antagonists in treating mood disorders and substance use disorders in humans.
Pleiotropic Effects of Kappa Opioid Receptor-Related Ligands in Non-human Primates.
TLDR
How non-human primates (NHP) studies facilitate the research and development of ligands targeting the KOR, effects of the endogenous opioid peptide, dynorphin A-(1-17), and its analogs in NHP, and pleiotropic effects and therapeutic applications of KOR-related ligands are highlighted.
Rapid-Onset Anti-Stress Effects of a Kappa-Opioid Receptor Antagonist, LY2795050, Against Immobility in an Open Space Swim Paradigm in Male and Female Mice
TLDR
These studies show that a novel KOR-antagonist can produce very rapid onset anti-immobility effects in this model of acute stress exposure, and may be of interest for medication development.
Analogs of the κ opioid receptor antagonist arodyn cyclized by ring-closing metathesis retain κ opioid receptor affinity, selectivity and κ opioid receptor antagonism
TLDR
The dynorphin (Dyn) A analog arodyn is a κ opioid receptor-selective antagonist, but as a linear peptide it is conformationally flexible and subject to metabolism by proteases, so both short- and long-range cyclizations via ring-closing metathesis (RCM) involving residues in both the N-terminal “message” and C-terminals “address” sequences were explored.
Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats
TLDR
It is suggested that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.
Regulation of Kappa Opioid Receptor Inactivation Depends on Sex and Cellular Site of Antagonist Action
TLDR
It is reported that norBNI does not work as effectively in female mice as in males because of estrogen regulation of G protein receptor kinase (GRK); pretreatment of ovary-intact female mice with the selective GRK2/3 inhibitor, Compound 101, made females equally sensitive to norBNi as males.
Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology
TLDR
Electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems are shown and demonstrate the value of characterizing compounds in native neuronal tissue and within disorder-relevant circuits implicated in neurobehavioral disorders.
Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice
TLDR
This study further implicates the λ-receptor system in ethologically relevant aspects of anhedonia, and confirms sexual dimorphism in some behavioral effects of novel κ-antagonists.
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By use of parallel chemistry coupled with physicochemical property design, a series of selective κ opioid antagonists have been discovered and 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan- 1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.
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