Blicker Luca, González-Cano Rafael, Laurini Erik, Nieto Francisco R, Schmidt Judith, Schepmann Dirk, Pricl Sabrina, Wünsch Bernhard
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Department of Pharmacology, Faculty of Medicine and Biomedical Research Center (Neurosciences Institute), Biosanitary Research Institute ibs. GRANADA, University of Granada, Avenida de la Investigación 11, Granada 18016, Spain.
J Med Chem. 2023 Apr 13;66(7):4999-5020. doi: 10.1021/acs.jmedchem.2c02081. Epub 2023 Mar 22.
Antagonists at σ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (), aminodiols were obtained and transformed into bicyclic and tricyclic ligands . Aminodiols showed higher σ affinity than the corresponding bicyclic and tricyclic derivatives . ()-configuration in the side chain of aminodiols ( and ) led to higher σ affinity than ()-configuration ( and ). 4-Benzylpiperidines (-series) revealed higher σ affinity than 4-phenylbutylamines (-series). Aminodiol showed very high σ affinity ( = 1.2 nM), excellent selectivity over σ receptors, and promising log (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the σ affinity and selectivity on an atomistic level. In the capsaicin assay, exhibited similar antiallodynic activity to the prototypical σ antagonist S1RA. The antiallodynic activity of was removed by co-application of the σ agonist PRE-084, proving σ antagonism being involved in the antiallodynic effect.
σ受体拮抗剂在治疗神经性疼痛方面具有巨大潜力。从单萜（-）-异蒲勒醇（）出发，获得了氨基二醇，并将其转化为双环和三环配体。氨基二醇显示出比相应的双环和三环衍生物更高的σ亲和力。氨基二醇（和）侧链中的（）-构型导致比（）-构型（和）更高的σ亲和力。4-苄基哌啶（-系列）显示出比4-苯基丁胺（-系列）更高的σ亲和力。氨基二醇显示出非常高的σ亲和力（= 1.2 nM），对σ受体具有出色的选择性，以及有前景的log（3.05）和亲脂性配体效率（5.87）值。进行了分子动力学模拟以在原子水平上分析σ亲和力和选择性。在辣椒素试验中，表现出与典型的σ拮抗剂S1RA相似的抗痛觉过敏活性。通过共同施用σ激动剂PRE-084消除了的抗痛觉过敏活性，证明σ拮抗作用参与了抗痛觉过敏作用。
