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1.
Neuropharmacology ; 257: 110037, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-38876309

ABSTRACT

Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for therapeutic purposes. Accordingly, navacaprant (NMRA-140) is a potent, selective KOR antagonist being evaluated as a treatment for major depressive disorder. In the present report, we have extended the pharmacological characterization of navacaprant by further demonstrating its selective KOR antagonist properties and confirming its lack of agonist activity at KORs and related targets involved in opioid-related abuse. Using CHO-K1 cells expressing human KOR, mu (MOR), or delta (DOR) opioid receptors, navacaprant demonstrated selective antagonist properties at KOR (IC50 = 0.029 µM) versus MOR (IC50 = 3.3 µM) and DOR (IC50 > 10 µM) in vitro. In vivo, navacaprant (10-30 mg/kg, i.p.) dose-dependently abolished KOR-agonist induced analgesia in the mouse tail-flick assay. Additionally, navacaprant (10, 30 mg/kg, p.o.) significantly reduced KOR agonist-stimulated prolactin release in mice and rats, confirming KOR antagonism in vivo. Navacaprant showed no agonist activity at any opioid receptor subtype (EC50 > 10 µM) in vitro and exhibited no analgesic effect in the tail-flick assays at doses ≤100 mg/kg, p.o. thereby confirming a lack of opioid receptor agonist activity in vivo. Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse.


Subject(s)
Analgesics, Opioid , Cricetulus , Receptors, Opioid, kappa , Receptors, Opioid, kappa/agonists , Receptors, Opioid, kappa/antagonists & inhibitors , Animals , CHO Cells , Humans , Male , Mice , Rats , Analgesics, Opioid/pharmacology , Cricetinae , Opioid-Related Disorders/drug therapy , Narcotic Antagonists/pharmacology , Dose-Response Relationship, Drug , Rats, Sprague-Dawley , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/antagonists & inhibitors , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Mice, Inbred C57BL , Dopamine/metabolism
2.
PLoS One ; 15(12): e0232864, 2020.
Article in English | MEDLINE | ID: mdl-33373369

ABSTRACT

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 µM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.


Subject(s)
Dopaminergic Neurons/drug effects , Membrane Potentials/drug effects , Receptors, Opioid, kappa/antagonists & inhibitors , Analgesics, Opioid/pharmacology , Animals , Benzamides/pharmacology , Biphenyl Compounds/pharmacology , Dopaminergic Neurons/metabolism , Electrophysiology , Enkephalin, D-Penicillamine (2,5)-/pharmacology , Male , Mesencephalon/metabolism , Narcotic Antagonists/pharmacology , Oxadiazoles/pharmacology , Patch-Clamp Techniques/methods , Piperidines/pharmacology , Pyrrolidines/pharmacology , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Sulfonamides/pharmacology , Ventral Tegmental Area/drug effects
3.
J Med Chem ; 62(4): 1761-1780, 2019 02 28.
Article in English | MEDLINE | ID: mdl-30707578

ABSTRACT

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-(tetrahydro-2 H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. CYM-53093 exhibited a broad selectivity over a panel of off-target proteins. This compound is in phase 1 clinical trials for the treatment of neuropsychiatric disorders wherein dynorphin is thought to contribute to the underlying pathophysiology.


Subject(s)
Aminoquinolines/therapeutic use , Narcotic Antagonists/therapeutic use , Oxadiazoles/therapeutic use , Piperidines/therapeutic use , Quinolines/therapeutic use , Receptors, Opioid, kappa/antagonists & inhibitors , Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacokinetics , Animals , Caco-2 Cells , Dogs , Drug Design , Escherichia coli/drug effects , Humans , Madin Darby Canine Kidney Cells , Male , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Migraine Disorders/drug therapy , Molecular Structure , Narcotic Antagonists/chemical synthesis , Narcotic Antagonists/pharmacokinetics , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats, Sprague-Dawley , Salmonella typhimurium/drug effects , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 23(5): 1456-61, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23347683

ABSTRACT

A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.


Subject(s)
Neurotransmitter Uptake Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Disease Models, Animal , Humans , Nerve Tissue Proteins/drug effects , Nerve Tissue Proteins/metabolism , Norepinephrine/antagonists & inhibitors , Norepinephrine/chemistry , Norepinephrine/metabolism , Pain/drug therapy , Pyrrolidines/chemical synthesis , Rats , Structure-Activity Relationship
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