Carr Daniel, Chin Christopher, Chacon Tiffany, Herawi Monijeh Khoja, Gonzalez Michael, West Ryan, Morisseau Christophe, Hammock Bruce D, Pecic Stevan, Kandasamy Ram
Department of Psychology, California State University, East Bay, Hayward, CA, USA.
Department of Chemistry and Biochemistry, California State University, Fullerton, Fullerton, CA, USA.
BBA Adv. 2024 Aug 8;6:100119. doi: 10.1016/j.bbadva.2024.100119. eCollection 2024.
Pain arising from trigeminal systems such as headache is common, debilitating, and current treatments (e.g., sumatriptan) are limited. New treatments that target novel mechanisms of action may be required to innovate both short- and long-term pain therapy. Fatty acid amide hydrolase and soluble epoxide hydrolase are two pain-related enzymes that regulate pain and inflammation via independent pathways. We have previously demonstrated that simultaneous inhibition of these enzymes using a novel dual inhibitor alleviates acute inflammatory pain in the hindpaw and does not depress wheel running in rats. Here, we expanded on these findings and performed structure-activity relationships of our lead compound, the 4-phenyl-thiazole-based dual inhibitor SW-17, to generate 18 analogs and tested them for their inhibition at both enzymes. Conversion of the sulfonamide group to a tertiary amine led to a general decrease in the potency for the sEH enzyme, while this change was well-tolerated at the FAAH enzyme yielding several strong inhibitors. Six selected inhibitors were evaluated in mouse and rat sEH inhibition assays and results showed a species difference, i.e. 4-phenyl-thiazole-based analogs are significantly less or not active in mouse sEH compared to human and rat enzymes. The most potent inhibitor, SW-17, was evaluated in a plasma stability assay in human and rat plasma and showed moderate stability. However, SW-17 did not alleviate orofacial inflammatory pain in female rats compared to the traditional anti-migraine agent sumatriptan. Although modification of 4-phenyl-thiazole-based dual inhibitor SW-17 changes potencies at both FAAH and sEH, these approaches may not produce antinociception against trigeminal pain. Key Words: polypharmacology, formalin, inflammation, enzyme inhibition, structure-activity relationship studies.
源自三叉神经系统的疼痛，如头痛，很常见且使人虚弱，而目前的治疗方法（如舒马曲坦）有限。可能需要针对新作用机制的新治疗方法来革新短期和长期疼痛治疗。脂肪酸酰胺水解酶和可溶性环氧化物水解酶是两种与疼痛相关的酶，它们通过独立途径调节疼痛和炎症。我们之前已经证明，使用新型双抑制剂同时抑制这些酶可减轻后爪的急性炎性疼痛，且不会抑制大鼠的转轮行为。在此，我们扩展了这些发现，并对我们的先导化合物、基于4-苯基噻唑的双抑制剂SW-17进行了构效关系研究，以生成18种类似物，并测试它们对这两种酶的抑制作用。将磺酰胺基团转化为叔胺导致sEH酶的效力普遍降低，而这种变化在FAAH酶中耐受性良好，产生了几种强效抑制剂。在小鼠和大鼠sEH抑制试验中评估了六种选定的抑制剂，结果显示存在物种差异，即与人和大鼠的酶相比，基于4-苯基噻唑的类似物在小鼠sEH中的活性显著较低或无活性。在人和大鼠血浆的血浆稳定性试验中评估了最有效的抑制剂SW-17，结果显示其稳定性适中。然而，与传统抗偏头痛药物舒马曲坦相比，SW-17并未减轻雌性大鼠的口面部炎性疼痛。尽管对基于4-苯基噻唑的双抑制剂SW-17进行修饰会改变其对FAAH和sEH的效力，但这些方法可能无法产生针对三叉神经痛的镇痛作用。关键词：多药理学、福尔马林、炎症、酶抑制、构效关系研究。
