e-52862 and Neuralgia

The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound

Topics: Animals; Binding Sites; Blood-Brain Barrier; Drug Design; Guinea Pigs; Half-Life; Humans; Microsomes, Liver; Molecular Dynamics Simulation; Neuralgia; Pain Management; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship; Rats; Receptors, sigma; Sigma-1 Receptor; Triazoles

Topics: Amides; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Guinea Pigs; Injections, Subcutaneous; Mice; Mice, Inbred ICR; Molecular Structure; Neuralgia; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Receptors, sigma; Sciatic Nerve; Sigma-1 Receptor; Structure-Activity Relationship

By use of the 6-hydroxypyridazinone framework, a new series of potent σ1 receptor ligands associated with pharmacological antineuropathic pain activity was synthesized and is described in this article. In vitro receptor binding studies revealed high σ1 receptor affinity (Ki σ1 = 1.4 nM) and excellent selectivity over not only σ2 receptor (1366-fold) but also other CNS targets (adrenergic, μ-opioid, sertonerigic receptors, etc.) for 2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)propoxy)pyridazin-3(2H)-one (compound 54). Compound 54 exhibited dose-dependent antiallodynic properties in mouse formalin model and rats chronic constriction injury (CCI) model of neuropathic pain. In addition, functional activity of compound 54 was evaluated using phenytoin and indicated that the compound was a σ1 receptor antagonist. Moreover, no motor impairments were found in rotarod tests at antiallodynic doses and no sedative side effect was evident in locomotor activity tests. Last but not least, good safety and favorable pharmacokinetic properties were also noted. These profiles suggest that compound 54 may be a member of a novel class of candidate drugs for treatment of neuropathic pain.

Topics: Analgesics, Non-Narcotic; Animals; Chemistry Techniques, Synthetic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Formaldehyde; Guinea Pigs; Ligands; Mice; Neuralgia; Pain Measurement; Pyridazines; Rats, Sprague-Dawley; Receptors, Opioid, delta; Rotarod Performance Test; Structure-Activity Relationship

The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain.

Topics: Animals; Behavior, Animal; Carbon Tetrachloride; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Mice; Molecular Structure; Motor Activity; Neuralgia; Neuroprotective Agents; Nociceptive Pain; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.

Topics: Animals; Brain; Female; Guinea Pigs; HEK293 Cells; Humans; Hyperalgesia; In Vitro Techniques; Male; Mice; Microsomes, Liver; Morpholines; Motor Activity; Neuralgia; Patch-Clamp Techniques; Pyrazoles; Radioligand Assay; Receptors, sigma; Sciatic Neuropathy; Sigma-1 Receptor; Structure-Activity Relationship