5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted κ-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine κ pharmacophore allows the fine-tuning of the pharmacodynamic and pharmacokinetic properties. The perhydroquinoxalines were synthesized stereoselectively using the concept of late stage diversification of the central building blocks 14. In addition to high κ-opioid receptor affinity they demonstrate high selectivity over μ, δ, σ1, σ2, and NMDA receptors. In the [35S]GTPγS assay full agonism was observed. Because of their high polarity, the secondary amines 14a (log D7.4=0.26) and 14b (log D7.4=0.21) did not penetrate an artificial blood-brain barrier. 14b was able to inhibit the spontaneous pain reaction after rectal mustard oil application to mice (ED50=2.35 mg/kg). This analgesic effect is attributed to activation of peripherally located κ receptors, since 14b did not affect centrally mediated referred allodynia and hyperalgesia.
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Enantiomeric N-substituted N-normetazocines: a comparative study of affinities at sigma, PCP, and mu opioid receptors
Synthesis and receptor binding of enantiomeric N-substituted cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamines as high-affinity sigma receptor ligands
Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands
Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction
kappa-Opioid activity of the four stereoisomers of the peripherally selective kappa-agonists, EMD 60,400 and EMD 61,753
A pharmacological profile of the novel, peripherally-selective kappa-opioid receptor agonist, EMD 61753
Antipodal alpha-N-(methyl through decyl)-N-normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans): in vitro and in vivo properties
A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines
Conformational analysis and automated receptor docking of selective arylacetamide-based kappa-opioid agonists
An improved low-permeability in vitro-model of the blood-brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol
Primary cultures of brain microvessel endothelial cells: a valid and flexible model to study drug transport through the blood-brain barrier in vitro
Methylated analogues of methyl (R)-4-(3,4-dichlorophenylacetyl)- 3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate (GR-89,696) as highly potent kappa-receptor agonists: stereoselective synthesis, opioid-receptor affinity, receptor selectivity, and functional studies
Novel sigma receptor ligands. Part 2. SAR of spiro[benzopyran-1,4'-piperidines] and spiro[benzofuran-1,4'-piperidines] with carbon substituents in position 3
FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): A peripheral efficacious kappa opioid agonist with unprecedented selectivity
Structural determinants of opioid activity in derivatives of 14-aminomorphinones: effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones
Synthesis and pharmacological evaluation of bicyclic SNC80 analogues with separated benzhydryl moiety
Novel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors
Effect of drug lipophilicity and ionization on permeability across the buccal mucosa: a technical note.
Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain
Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study
Conformationally constrained kappa receptor agonists: stereoselective synthesis and pharmacological evaluation of 6,8-diazabicyclo[3.2.2]nonane derivatives
Use of the GTPγS ([35S]GTPγS and Eu-GTPγS) binding assay for analysis of ligand potency and efficacy at G protein-coupled receptors.
Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists
Impact of manganese on and transfer across blood-brain and blood-cerebrospinal fluid barrier in vitro.
Combination of cyclohexane and piperazine based κ-opioid receptor agonists: Synthesis and pharmacological evaluation of trans,trans-configured perhydroquinoxalines
Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design
Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity in Vivo
Stereoselective synthesis of conformationally restricted KOR agonists based on the 2,5-diazabicyclo[2.2.2]octane scaffold
Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]-quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects
Enantiomerically Pure Quinoline-Based κ-Opioid Receptor Agonists: Chemoenzymatic Synthesis and Pharmacological Evaluation.
Modulation of cocaine-related behaviors by low doses of the potent KOR agonist nalfurafine in male C57BL6 mice
Diastereoselective Synthesis of Cyclic Five-Membered trans,trans-Configured Nitrodiols by Double Henry Reaction of 1,4-Dialdehydes
Design and synthesis of N‑(benzylpiperidinyl)‑4‑fluorobenzamide: A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonism
Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors.
Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline-Based κ-Opioid Receptor (KOR) Agonists Designed for PET Studies.
Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B.
The effect of carbonyl on the isomerization of a galanthan ring system and total synthesis of (±)-β-lycorane.
Synthesis and pharmacological evaluation of [(3)H]HS665, a novel, highly selective radioligand for the kappa opioid receptor
Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation
Synthesis, Biological, and Structural Explorations of New Zwitterionic Derivatives of 14- O-Methyloxymorphone, as Potent μ/δ Opioid Agonists and Peripherally Selective Antinociceptives
6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand
Methylation Products of 6β- N-Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators
Signaling Properties of Structurally Diverse Kappa Opioid Receptor Ligands: Toward in Vitro Models of in Vivo Responses
Synthesis and pharmacological evaluation of enantiomerically pure endo-configured KOR agonists with 2-azabicyclo[3.2.1]octane scaffold.
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