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ChemInform Abstract: Nonpsychotropic Synthetic Cannabinoids as Therapeutic Agents
Abstract
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Although cannabis has been used for thousands of years for medical and recreational purposes, the debate on its introduction as a medical product has only recently begun. That discussion was preceded by the discovery and explanation of the active components in cannabis on the one hand, and the discovery of the endocannabinoid system in mammals on the other. Numerous studies over the past thirty years have focused on their further examination, and scarce clinical studies show the beneficial effects of cannabis on the wide spectrum of diseases. The question is why, thirty years after the discovery of the endocannabinoid system and the CB1 and CB2 receptors, as well as the positive results in cannabis administration in a wide range of diseases, extensive clinical studies and relevant explanations are still lacking. On the other hand, one may wonder if something important is being denied to patients who might find cannabis use beneficial? Therefore, it is important to analyze several different problems. What is the subject of the dispute, and which cannabis derivatives are allowed? Why do we not have relevant clinical studies, that is, all of those are of a very limited extent? How are clinical studies conducted? To whom are these derivatives intended and are there ethical dilemmas regarding their use?
The development of antiemetic drugs has been one of the most rewarding areas of oncologic research, since therapeutic advances in this area can result in immediate improvement in the quality of life for patients undergoing chemotherapy. Antiemetic therapy has progressed dramatically during the past decade and a half. Fifteen years ago, patients receiving cisplatin for the first time had a median of 12 vomiting episodes within the first 24 hours, whereas now more than 50 percent of such patients have no vomiting episodes at all. Theoretical and clinical challenges remain, however, in the effort to control chemotherapy-induced emesis. The mechanisms of anticipatory vomiting and delayed vomiting are still not understood, and consistently effective therapeutic approaches to these problems have yet to be developed.
The negative and positive enantiomers of 7-hydroxy-delta 6-tetrahydrocannabinol-dimethylheptyl (designated HU-210 and HU-211 respectively) differentially affect undifferentiated and differentiating cultured pheochromocytoma cells (PC-12 cells). In general, cell viability and cell proliferation were suppressed to a much greater extent with HU-210 than with HU-211 in differentiating cells. The effects of these synthetic cannabinoids on the cytoskeleton of PC-12 cells were examined by epifluorescence and confocal microscopy. In both undifferentiated and differentiating PC-12 cells, HU-211 has little effect on the cytoarchitecture whereas HU-210 disrupts the distribution of microtubules and microfilaments. Vacuoles (2-4 microns) were evident in the cytoplasm of HU-210-treated cells but not in the cytoplasm of HU-211-treated cells or in vehicle controls. Tubulin and actin mRNA levels were reduced to 5 and 40%, respectively (relative to untreated controls) in 10 microns HU-210-treated cells whereas the same concentration of HU-211 reduced tubulin and actin mRNA levels to 90 and 95%, respectively. A comparison of the effects of the paired enantiomers and delta 1-THC on the cellular parameters studied reveals that in differentiating cells the action of delta 1-THC is intermediate between that of HU-210 and HU-211. This study demonstrates that compared to HU-210 and delta 1-THC the positive enantiomer HU-211 has little cellular activity.
Many of our present medicines are derived directly or indirectly from higher plants. While several classic plant drugs have lost much ground to synthetic competitors, others have gained a new investigational or therapeutical status in recent years. In addition, a number of novel plant-derived substances have entered into Western drug markets. Clinical plant-based research has made particularly rewarding progress in the important fields of anticancer (e.g. taxoids and camptothecins) and antimalarial (e.g. artemisinin compounds) therapies. In addition to purified plant-derived drugs, there is an enormous market for crude herbal medicines. Natural product research can often be guided by ethnopharmacological knowledge, and it can make substantial contributions to drug innovation by providing novel chemical structures and/or mechanisms of action. In the end, however, both plant-derived drugs and crude herbal medicines have to take the same pharmacoeconomic hurdle that has become important for new synthetic pharmaceuticals.
Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor.
Some recent scientific advances in the study of the cannabinoids are outlined. The mode of action of marihuana and the cannabinoids has now been described. They belong to a new class of drug that acts on a hitherto undescribed neuro-physiological system. An endogenous neurotransmitter or neuromodulator for this system has been isolated, identified and named "anandamide". These findings throw new light and imbue new confidence for the future of the therapeutic application of compounds derived from and related to the cannabinoids and anandamide. An outline is also provided of the current knowledge and future potential of cannabinoids in therapeutics. The effect of the current legal classification of the cannabinoids on the research and development of these compounds is discussed.
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