e-52862 and Pain

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4

Topics: Analgesics; Animals; Cell Membrane Permeability; Disease Models, Animal; Female; Half-Life; Humans; Ligands; Male; Mice; Microsomes, Liver; Pain; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship; Triazoles

A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ

Topics: Amides; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Humans; Mice; Molecular Structure; Narcotic Antagonists; Pain; Receptors, Opioid, mu; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ

Topics: Alkanes; Analgesics; Analgesics, Opioid; Animals; Humans; Male; Mice; Models, Molecular; Pain; Pain Management; Receptors, Opioid, mu; Receptors, sigma; Sigma-1 Receptor; Spiro Compounds

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ

Topics: Administration, Oral; Analgesics, Opioid; Animals; Binding Sites; Blood-Brain Barrier; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Half-Life; Ligands; Male; Mice; Molecular Dynamics Simulation; Pain; Receptors, Opioid, mu; Receptors, sigma; Sigma-1 Receptor; Spiro Compounds; Structure-Activity Relationship

The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1

Topics: Analgesics; Animals; Caco-2 Cells; Humans; Mice; Molecular Structure; Pain; Piperazines; Pyrazoles; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

The synthesis and biological evaluation of new series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as selective sigma-1 receptor (σ1R) antagonists are reported. The receptor affinities of new compounds were evaluated in vitro in σ1 and σ2 receptor binding assays. The structure-active relationship study leads us to the most promising compound: 2-(4-chlorophenyl)-4-(3-(4-methylpiperidin-1-yl)propoxy)-5,6,7,8-tetra-hydroquinazoline (33). Compound 33 has exerted nanomolar affinity for σ1R (Kiσ1=15.6 nM) and high σ1/σ2 selectivity (Kiσ2 >2000 nM), and identified to be a σ1R antagonist. In animal model, compound 33 exhibited dose dependent anti-nociceptive effects in the formalin test. These results suggest that compound 33 could be a potent analgesic for pain treatment.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Guinea Pigs; Molecular Structure; Pain; Pyrimidines; Quinazolines; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.

Topics: Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Injections, Intraperitoneal; Isoxazoles; Ligands; Mice; Mice, Inbred Strains; Molecular Structure; Pain; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship