Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia, Bulgaria.
Drug Dev Res. 2024 Aug;85(5):e22236. doi: 10.1002/ddr.22236.
The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.
新型肉桂酸 (CA)（H4-CA、H5-CA 和 H7-CA）和咖啡酸 (KA)（H4-KA、H5-KA 和 H7-KA）脑啡肽类似物最近已被合成，并对其反式异构体的抗惊厥和镇痛活性进行了测试。在本研究中，测试了这些化合物的顺式形式，并将其与在小鼠惊厥和疼痛测试中的反式异构体进行了比较。顺式-H5-CA 和 H7-CA 化合物对精神运动性惊厥有效，而反式异构体无效。6-Hz 测试中，顺式和反式 KA 异构体均无效。在最大电休克（MES）测试中，顺式异构体分别显示出比 CA 和 KA 缀合物的反式异构体更优的抗惊厥活性。顺式-H5-CA 和顺式-H5-KA 对惊厥传播的抑制作用被κ 阿片受体（KOR）拮抗剂逆转。纳洛酮和纳曲吲哚无效。CA 缀合物的顺式异构体和顺式-H7-KA 产生的镇痛作用明显强于其反式异构体。顺式-H5-CA 的镇痛作用在急性阶段被纳洛酮阻断，在福尔马林试验的炎症阶段被纳洛酮和 KOR 拮抗剂阻断。阿片受体阻断剂不能消除 KA 缀合物的镇痛作用。测试的缀合物均未影响热痛觉阈值。对接分析的结果也表明，与 CA 和 KA 缀合物的顺式异构体与阿片受体活性相关的是一种特定于模型的机制。我们的研究结果为进一步开发新型与阿片类相关的抗惊厥和镇痛治疗方法铺平了道路。
