Synthesis And SAR Studies Of 3-Alkoxyisoxazoles As σ1 Receptor Ligands

Sigma receptor is a unique receptor with two subtypes:σ1 and σ2. The σ1 receptor is a 223 amino acid protein with two transmembrane domains located at the mitochondrial-associated endoplasmic reticulum membrane. While the σ2 receptor is overexpressed in aggressive tumor cells and as such has been proposed as a biomarker for tumor cell proliferation. σ1 receptor mainly distributed in the central nervous system(CNS), especially in the hypothalamus, cortex, olfactory bulb and midbrain. σ1 receptor has been known to modulate dopamine, acetylcholine,5-hydroxytryptamine (5-HT), and opioid receptors. Various reports have demonstrated σ1 receptor is associated with the mental disorders and cognitive function, It is a potential target of treatment for many CNS disorders (such as schizophrenia, depression), the cocaine addiction and neuropathic pain.Compounds based on the lead compound 15 (Ki, σ1=4.1 nM, σ2=1312 nM, DAT=373 nM, NET=203 nM) were synthesized for structure-activity relationship study in order to improve the activity and selectivity. According to the σ1 receptor pharmacophore model (a basic amino group and one hydrophobic region at a 6-10 A from the basic amino group),26 3-alkoxyisoxazole compounds were synthesized and their binding affinities at σ receptors were evaluated. Most of the compounds were found to show high affinities (Ki=2.4-358 nM) and the selectivity over σ2 receptor. Moreover, selected 12 compounds were all found to show no obvious binding affinity at the DAT, NET, SERT. The caculated log BB values and in vitro PAMPA-BBB data suggested that compounds are likely to exihibit moderate BBB permeability. Functional studies suggested that most compounds are al antagonists. Finally the thesis put forward prospect of the development of 3-alkoxyisoxazoles σ1 receptor ligands with high affinities and selectivities.