Schirris Tom J J, Ritschel Tina, Herma Renkema G, Willems Peter H G M, Smeitink Jan A M, Russel Frans G M
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands.
Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands.
Sci Rep. 2015 Sep 29;5:14533. doi: 10.1038/srep14533.
Cannabinoid receptor 1 (CB1R) antagonists appear to be promising drugs for the treatment of obesity, however, serious side effects have hampered their clinical application. Rimonabant, the first in class CB1R antagonist, was withdrawn from the market because of psychiatric side effects. This has led to the search for more peripherally restricted CB1R antagonists, one of which is ibipinabant. However, this 3,4-diarylpyrazoline derivative showed muscle toxicity in a pre-clinical dog study with mitochondrial dysfunction. Here, we studied the molecular mechanism by which ibipinabant induces mitochondrial toxicity. We observed a strong cytotoxic potency of ibipinabant in C2C12 myoblasts. Functional characterization of mitochondria revealed increased cellular reactive oxygen species generation and a decreased ATP production capacity, without effects on the catalytic activities of mitochondrial enzyme complexes I-V or the complex specific-driven oxygen consumption. Using in silico off-target prediction modelling, combined with in vitro validation in isolated mitochondria and mitoplasts, we identified adenine nucleotide translocase (ANT)-dependent mitochondrial ADP/ATP exchange as a novel molecular mechanism underlying ibipinabant-induced toxicity. Minor structural modification of ibipinabant could abolish ANT inhibition leading to a decreased cytotoxic potency, as observed with the ibipinabant derivative CB23. Our results will be instrumental in the development of new types of safer CB1R antagonists.
大麻素受体1（CB1R）拮抗剂似乎是治疗肥胖症的有前景的药物，然而，严重的副作用阻碍了它们的临床应用。利莫那班是首个上市的CB1R拮抗剂，因其精神方面的副作用而退市。这促使人们寻找更具外周选择性的CB1R拮抗剂，其中之一是伊比班特。然而，这种3,4-二芳基吡唑啉衍生物在一项临床前犬类研究中显示出肌肉毒性，并伴有线粒体功能障碍。在此，我们研究了伊比班特诱导线粒体毒性的分子机制。我们观察到伊比班特在C2C12成肌细胞中具有很强的细胞毒性。线粒体的功能特性显示细胞活性氧生成增加，ATP生成能力下降，但对线粒体酶复合物I-V的催化活性或复合物特异性驱动的氧消耗没有影响。通过计算机脱靶预测建模，并结合在分离的线粒体和线粒体膜间腔中的体外验证，我们确定腺嘌呤核苷酸转位酶（ANT）依赖性线粒体ADP/ATP交换是伊比班特诱导毒性的一种新的分子机制。伊比班特的微小结构修饰可以消除对ANT的抑制作用，从而降低细胞毒性，伊比班特衍生物CB23的情况就是如此。我们的研究结果将有助于开发新型更安全的CB1R拮抗剂。
