SA4503, a potent sigma(1) receptor agonist, is reported as having 103-fold higher affinity for sigma(1) (IC(50) = 17.4 nM) than sigma(2) (IC(50) = 1,784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on sigma(1)/sigma(2) selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for sigma(2) sites (IC(50) = 2.11 nM) and a weaker interaction with sigma(1) sites (IC(50) = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to sigma(1) receptors in animal and human brain in vivo. We prepared SA4503 and FE-SA4503 as reference compounds for radioligand development efforts. In our hands, SA4503 is 14-fold selective for sigma(1) (K(i) = 4.6 nM) over sigma(2) (K(i) = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for sigma(1) (K(i) = 8.0 nM) over sigma(2) (K(i) = 113.2 nM) receptors. The main differences from previously reported values stem from sigma(2) affinity determinations. This protocol, displacement of [(3)H]DTG binding to sigma(2) sites using (+)-pentazocine (200 nM) to mask sigma(1) sites, was validated by the proper rank order of sigma(2) inhibitory potencies shown by a panel of additional ligands: ifenprodil > haloperidol > DTG >> (+)-pentazocine. Robust Pearson correlation (r = 1.0, P = 0.002; slope = 0.97) was observed for our pK(i) values against those from a prior study by others. The findings have bearing on structure-activity relationships for this active series, and on conclusions that might be drawn from experiments relying upon defined sigma(1)/sigma(2) binding selectivity.
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http://dx.doi.org/10.1002/syn.20253 | DOI Listing |
RSC Med Chem
November 2024
Department of Drug and Health Sciences, University of Catania Viale A. Doria 6 95125 Catania Italy (+39) 095 7384273.
Inflammatory pain represents one of the unmet clinical needs for patients, as conventional therapies cause several side effects. Recently, new targets involved in inflammatory pain modulation have been identified, including the sigma-1 receptor (σ1R). Selective σ1R antagonists have demonstrated analgesic efficacy in acute and chronic inflammatory pain models.
View Article and Find Full Text PDFAnal Chem
January 2025
Instituto de Biomedicina y Genética Molecular, Unidad de Excelencia, University of Valladolid-CSIC, Valladolid 47003, Spain.
Lipid rafts are liquid-ordered domains in which specific enzymes and receptors are located. These membrane platforms play crucial roles in a variety of signaling pathways. Alterations in the lipid environment, such as those elicited by oxidative stress, can lead to important functional disruptions in membrane proteins.
View Article and Find Full Text PDFEur J Med Chem
January 2025
Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstraße 48, D-48149, Münster, Germany. Electronic address:
The σ receptor plays a key role in the regulation of various processes in the human body; it is involved in the development of neurodegenerative and neuropsychiatric diseases and is overexpressed in several human tumors rendering it an important target for potential drug candidates. In this project, spirocyclic σ receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ receptor affinity and selectivity over related targets. The σ affinity of the ligands was correlated with their lipophilicity (logD value) giving insight into their lipophilic ligand efficiency (LLE).
View Article and Find Full Text PDFSci Rep
October 2024
College of Mining Engineering, Anhui University of Science & Technology, Huainan, 232001, Anhui, China.
Deep rock masses are typically in complex stress states, and research on the evolution of their strain energy density is of highly important for understanding their failure characteristics. In this work, a true triaxial stress‒balanced unloading test is designed to analyze the u and u evolution of sandstone under true triaxial compression conditions. The study results indicate that as σ increases, the elastic strain decreases in the σ and σ directions, whereas the residual strain progressively increases, and the magnitude of decrease in elastic strain exceeds the magnitude of increase in residual strain.
View Article and Find Full Text PDFBrain Res Bull
October 2024
Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address:
Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I-receptor agonist LNP599 and whether the attenuation involves co-activation of α-adrenoceptors. Spared nerve injury (SNI) model of neuropathy was used to induce mechanical hypersensitivity in male and female rats with a chronic catheter for intrathecal drug administrations. Mechanical sensitivity and heat nociception were assessed behaviorally in the injured limb.
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