Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia, Bulgaria.
Department of Analytical Chemistry, University of Chemical Technology and Metallurgy, Sofia, Bulgaria.
Arch Pharm (Weinheim). 2024 Jul;357(7):e2400052. doi: 10.1002/ardp.202400052. Epub 2024 Apr 5.
Some new hemorphin-4 analogs with structures of Xxx-Pro-Trp-Thr-NH and Tyr-Yyy-Trp-Thr-NH, where Xxx is 2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid or 2-amino-3-(4-dibenzylamino-2,6-dimethylphenyl)propanoic acid, and Yyy is (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical and spectral analyses. In vivo anticonvulsant and antinociceptive activities of peptide derivatives were studied after intracerebroventricular injection in mice. The therapeutic effects of the modified peptides on seizures and pain in mice were evaluated to provide valuable insights into the potential applications of the novel compounds. Electrochemical characterization showed that the compounds behave as weak protolytes and that they are in a soluble, stable molecular form at physiological pH values. The antioxidant activity of the peptides was evaluated with voltammetric analyses, which were confirmed by applying the 2,2-Diphenyl-1-picrylhydrazyl method. The compounds showed satisfactory results regarding their structural stability, reaching the desired centers for the manifestation of biological activity without hydrolysis processes at 37°C and physiological pH. Dm-H4 and H4-P1 exhibited 100% and 83% potency to suppress the psychomotor seizures in the 6-Hz test compared to 67% activity of H4. Notably, only the H4-P1 had efficacy in blocking the tonic component in the maximal electroshock test with a potency comparable to H4. All investigated peptides containing unnatural conformationally restricted amino acids showed antinociceptive effects. The analogs Db-H4 and H4-P1 showed the most pronounced and long-lasting effect in both experimental models of pain induced by thermal and chemical stimuli. Dm-H4 produced a dose-dependent thermal antinociception and H4-P2 inhibited only formalin-induced pain behavior.
一些新的血红蛋白-4 类似物具有 Xxx-Pro-Trp-Thr-NH 和 Tyr-Yyy-Trp-Thr-NH 的结构,其中 Xxx 是 2-氨基-3-(4-羟基-2,6-二甲基苯基)丙酸或 2-氨基-3-(4-二苄基氨基-2,6-二甲基苯基)丙酸,Yyy 是(2S,4S)-4-氨基-吡咯烷-2-羧酸,通过电化学和光谱分析进行了合成和表征。在体内,通过向小鼠脑室内注射研究了肽衍生物的抗惊厥和抗伤害作用。评估了修饰肽对小鼠癫痫发作和疼痛的治疗效果,为新型化合物的潜在应用提供了有价值的见解。电化学表征表明,这些化合物表现为弱质子酸,并且在生理 pH 值下以可溶、稳定的分子形式存在。通过伏安分析评估了肽的抗氧化活性,并通过应用 2,2-二苯基-1-苦基肼法进行了确认。这些化合物在结构稳定性方面表现出令人满意的结果,在 37°C 和生理 pH 下没有水解过程,达到了表现生物活性的所需中心。与 H4 相比,Dm-H4 和 H4-P1 分别在 6-Hz 测试中显示出 100%和 83%的抑制精神运动性癫痫发作的效力,而 H4 的活性为 67%。值得注意的是,只有 H4-P1 在最大电休克测试中具有阻断强直性成分的功效,其效力与 H4 相当。所有含有非天然构象受限氨基酸的研究肽均表现出镇痛作用。类似物 Db-H4 和 H4-P1 在热刺激和化学刺激引起的两种疼痛模型中均表现出最显著和持久的作用。Dm-H4 产生剂量依赖性的热镇痛作用,而 H4-P2 仅抑制福尔马林诱导的疼痛行为。