Forskolin

Mechanism of action

Forskolin is used in biochemistry experiments to raise levels of cyclic AMP (cAMP) in studies of cell physiology. Forskolin activates the enzyme adenylyl cyclase and increases intracellular levels of cAMP. cAMP is an important second messenger necessary for the proper biological response of cells to hormones and other extracellular signals. It is required for cell communication in the hypothalamus-pituitary gland axis, and for the feedback control of hormones via induction of corticotropin-releasing factor gene transcription. Cyclic AMP acts by activating cAMP-sensitive pathways such as protein kinase A and EPAC1.

Chemistry

It is defined as a category 4 chemical with acute dermal toxicity based on 2012 OSHA Hazard Communication Standard (29 CFR 1910.1200).

Derivatives

Its derivatives include colforsin daropate, NKH477, and FSK88, which may be more potent than forskolin at raising cAMP. These derivatives may have pharmaceutical utility against bronchoconstriction and heart failure.

Chemical synthesis

A total chemical synthesis has been reported. The key step of this chemical synthesis is photocyclization of a synthetic intermediate in presence of oxygen and methylene blue, followed by a singlet oxygen Diels-Alder reaction.

Biosynthesis

The heterocyclic ring is synthesized after the formation of the trans-fused carbon ring systems formed by a carbocation mediated cyclization. The remaining tertiary carbocation is quenched by a molecule of water. After deprotonation, the remaining hydroxy group is free to form the heterocyclic ring. This cyclization can occur either by attack of the alcohol oxygen onto the allylic carbocation formed by loss of diphosphate, or by an analogous SN2'-like displacement of the diphosphate. This forms the core ring system A of forskolin.

The remaining modifications of the core ring system A can putatively be understood as a series of oxidation reactions to form a poly-ol B which is then further oxidized and esterified to form the ketone and acetate ester moieties seen in forskolin. However, because the biosynthetic gene cluster has not been described, this putative synthesis could be incorrect in the sequence of oxidation/esterification events, which could occur in almost any order.

Weight loss

Although forskolin has been used in preliminary weight loss research, the low quality of the studies and inconclusive results prevented any determination of effects.

References

References

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2. (20 November 2023). "Forskolin". Drugs.com.
3. (January 2012). "Forskolin and derivatives as tools for studying the role of cAMP.". Die Pharmazie.
4. (July 2011). "Signal transduction in the hypothalamic corticotropin-releasing factor system and its clinical implications.". Stress.
5. (27 September 2024). "Targetmol Forskolin SDS".
6. (May 1999). "Stimulation of adenylyl cyclase and induction of brain-derived neurotrophic factor and TrkB mRNA by NKH477, a novel and potent forskolin derivative". [[Journal of Neurochemistry]].
7. (November 2006). "A forskolin derivative, FSK88, induces apoptosis in human gastric cancer BGC823 cells through caspase activation involving regulation of Bcl-2 family gene expression, dissipation of mitochondrial membrane potential and cytochrome c release". [[Cell Biology International]].
8. (April 2002). "Intravenous colforsin daropate, a water-soluble forskolin derivative, prevents thiamylal-fentanyl-induced bronchoconstriction in humans". [[Critical Care Medicine]].
9. (July 1995). "Effects of NKH477, a water-soluble forskolin derivative, on cardiac function in rats with chronic heart failure after myocardial infarction". [[The Journal of Pharmacology and Experimental Therapeutics]].
10. (May 2022). "The First Total Synthesis of (±)-Forskolin". Synfacts.
11. Dewick, P. M.. (2009). "Medicinal Natural Products". Wiley.
12. (April 2019). "Nutritionist and obesity: brief overview on efficacy, safety, and drug interactions of the main weight-loss dietary supplements". International Journal of Obesity Supplements.