WLB-87848, a Selective σ 1 Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity

The synthesis and pharmacological activity of a new series of thieno[2,3- ]pyrimidin-4(3 )-one derivatives as sigma-1 receptor (σ R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ R agonist ( ) that contains a free NH group as po...

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Published in:Journal of medicinal chemistry 2024-06, Vol.67 (11), p.9150
Main Authors: Christmann, Ute, Garriga, Lourdes, Llorente, Ana Virginia, Díaz, José Luis, Pascual, Rosalía, Bordas, Magda, Dordal, Albert, Porras, Mónica, Yeste, Sandra, Reinoso, Raquel F, Vela, José Miguel, Almansa, Carmen
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - metabolism
Animals
Cell Survival - drug effects
Hippocampus - drug effects
Hippocampus - metabolism
Humans
Male
Memory Disorders - drug therapy
Neurons - drug effects
Neurons - metabolism
Neuroprotective Agents - chemical synthesis
Neuroprotective Agents - chemistry
Neuroprotective Agents - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Pyrimidinones - chemical synthesis
Pyrimidinones - chemistry
Pyrimidinones - pharmacology
Rats
Rats, Wistar
Receptors, sigma - agonists
Receptors, sigma - metabolism
Sigma-1 Receptor
Structure-Activity Relationship
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Summary:The synthesis and pharmacological activity of a new series of thieno[2,3- ]pyrimidin-4(3 )-one derivatives as sigma-1 receptor (σ R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ R agonist ( ) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making (WLB-87848) an interesting candidate for neuroprotection.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.4c00288