Abstract
Herein we reported a series of 14 novel derivatives based on the N-cyclobutylaminoethoxyisoxazole scaffold. In vitro binding studies of these compounds demonstrated their low nanomolar to subnanomolar potencies as σ1 receptor ligands, with moderate to excellent selectivity over the σ2 receptor as represented by compounds 17–30. The majority of the derivatives scored high (>4.7) in the CNS MPO appraisal system, indicating their high likelihood in penetrating the blood–brain barrier. A number of these compounds exhibited significant neurite outgrowth efficacy in N1E-115 neuronal cells and displayed excellent selectivity for σ1 receptors over the selected endogenous neurotransmitter transporters, such as DAT, NET and SERT. Among the mini-series, compound 28 (Ki σ1 = 0.2 nM, Ki σ2 = 198 nM, CNS MPO score = 5.4) emerged as a promising selective σ1 receptor ligand that warrants its further evaluation as a potential therapeutic for neurodegenerative diseases.
Highlights
The activation of s1 receptor leads to the transfer of cholesterol, ceramides and essential amino acids that are essential for the growth and proliferation of the neurons, along with an increased gene expression of speci c protein and synthesis of various growth factors involved in neuronal outgrowth.[16,17,18]
14 novel derivatives based on the N-cyclobutylaminoethoxyisoxazole scaffold were designed and synthesized
central nervous system multiparameter optimization (CNS MPO) scores were calculated for predicting their blood–brain barrier permeability and the results showed most of derivatives obtained favourable CNS MPO scores greater than 4
Summary
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are caused by the progressive loss of neuronal integrity or acute neuron injury such as stroke or trauma in the brain and spinal cord.[1,2,3] Current therapeutic strategies for neurodegenerative diseases are mainly aimed to decrease CNS neuron damage or brain dysfunction by conferring neuroprotection and neurogenesis.[4,5] the development of effective therapeutic medicine or discovery of new biological targets with neurogenesis activities remains an urgent need in the treatment of neurodegenerative diseases. The structure indicated that the human s1 receptor has a trimeric architecture with a single transmembrane domain.[10] The literature reports to date indicate that s1 receptor is considered as chaperonin to modulate signaling pathways of ER–mitochondrion such as Ca2+, K+, and NMDA and IP3 receptors, playing an important role in healthy CNS functioning.[11,12,13] In particular, neurogenesis efficacy of brain penetrant s1 receptor ligands is of a considerable interest, which has been attributed to the s1 receptor's role in the modulation of cellular trafficking.[14,15] The activation of s1 receptor leads to the transfer of cholesterol, ceramides and essential amino acids that are essential for the growth and proliferation of the neurons, along with an increased gene expression of speci c protein and synthesis of various growth factors involved in neuronal outgrowth.[16,17,18] neurogenesis function was reported to be subdued in the hippocampus of s1 receptorknockout animals.[19]. Studies of the N-cyclobutylaminoethoxyisoxazole as s1 receptor ligands and their cellular evaluation in neurite outgrowth assay
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