Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: KEGG:D05731 (Rimonabant)
 326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cannabinoid Receptor 1 (CB1) has been initially described as the receptor for Delta-9-Tetrahydrocannabinol in the central nervous system (CNS), mediating retrograde synaptic signaling of the endocannabinoid system. Beside its expression in various CNS regions, CB1 is ubiquituous in peripheral tissues, where it mediates, among other activities, the cell's energy homeostasis. We sought to examine the role of CB1 in the context of the evolutionarily conserved autophagic machinery, a main constituent of the regulation of the intracellular energy status. Manipulating CB1 by siRNA knockdown in mammalian cells caused an elevated autophagic flux, while the expression of autophagy-related genes remained unaltered. Pharmacological inhibition of CB1 activity using Rimonabant likewise caused an elevated autophagic flux, which was independent of the mammalian target of rapamycin complex 1, a major switch in the control of canonical autophagy. In addition, knocking down coiled-coil myosin-like BCL2-interacting protein 1, the key-protein of the second canonical autophagy control complex, was insufficient to reduce the elevated autophagic flux induced by Rimonabant. Interestingly, lysosomal activity is not altered, suggesting a specific effect of CB1 on the regulation of autophagic flux. We conclude that CB1 activity affects the autophagic flux independently of the two major canonic regulation complexes controlling autophagic vesicle formation. Regulation of the autophagic flux in certain physiological situations such as an imbalance of nutrient supply as well as in pathological stages is of major importance for neuronal and non-neuronal cells. CB1 (Cannabinoid receptor 1) affects the metabolism of cells directly. In this study, we provide evidence that CB1 signaling has a direct influence on autophagy which might help the cell to find the right adjustment to different metabolic states and CB1 activity exerts its modulatory action independent of the canonical mTOR- and BECLIN1-complexes regulating autophagy.
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PMID:Cannabinoid receptor 1 modulates the autophagic flux independent of mTOR- and BECLIN1-complex. 2506 92

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.
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PMID:Mitochondrial ADP/ATP exchange inhibition: a novel off-target mechanism underlying ibipinabant-induced myotoxicity. 2641 58