Forskolin (coleonol) is a

labdane Labdane is a natural bicyclic diterpene. It forms the structural core for a wide variety of natural products collectively known as ''labdanes'' or ''labdane diterpenes''. The labdanes were so named because the first members of the class were ori ...

diterpene Diterpenes are a class of chemical compounds composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being ...

produced by the plant ''

Coleus barbatus ''Coleus barbatus'', also known by the synonyms ''Plectranthus barbatus'' and incorrectly ''Coleus forskalaei'' (and other spellings of this epithet), is a tropical perennial plant related to the typical coleus species. It produces forskolin, an ...

'' (Blue Spur Flower). Other names include pashanabhedi, Indian coleus, makandi, HL-362, mao hou qiao rui hua. As with other members of the large

class of plant metabolites, forskolin is derived from

geranylgeranyl pyrophosphate Geranylgeranyl pyrophosphate is an intermediate in the biosynthesis of diterpenes and di terpenoids. It is also the precursor to carotenoids, gibberellins, tocopherols, and chlorophylls. It is also a precursor to geranylgeranylated proteins, wh ...

(GGPP). Forskolin contains some unique functional elements, including the presence of a

tetrahydropyran Tetrahydropyran (THP) is the organic compound consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. It is named by reference to pyran, which contains two double bonds, and may be produced from it by addi ...

-derived

heterocyclic ring A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...

. Forskolin is commonly used in laboratory research to increase levels of

cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal tra ...

by stimulation of

adenylate cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

Mechanism of action

Forskolin is commonly used in biochemistry to raise levels of

(cAMP) in the study and research of

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

physiology. Forskolin activates the enzyme

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

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 In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...

and EPAC1.

Chemistry

Derivatives

Its derivatives include

colforsin daropate Colforsin daropate is a carboxylic ester derived from the condensation of forskolin (colforsin) with ''N'',''N''-dimethyl-β-alanine. Its water-soluble hydrochloride salt ( NKH 477) is an adenylyl cyclase activator which has been studied for its ...

, NKH477, and FSK88, which may be more potent than forskolin at raising cAMP. These derivatives may have pharmaceutical utility against

bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Causes The condition has a number of causes, the most common be ...

and heart failure.

Chemical Synthesis

A total chemical synthesis has been reported. The key step of this chemial 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 A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...

. The remaining tertiary carbocation is quenched by a molecule of water. After

deprotonation Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...

, 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 In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...

, or by an analogous S_N2'-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 In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

to form the ketone and

acetate ester An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called a ...

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.

Fat loss

In animals, forskolin, or extracts of ''

'' containing forskolin, reduce food intake, body weight, and fat mass. In humans, forskolin reduces body fat mass while increasing lean body mass. In mice, extracts of '' Coleus forskohlii'' exhibited dose-dependent liver toxicity although purified forskolin did not exhibit liver toxicity.

Other

Forskolin has been used in

traditional medicine Traditional medicine (also known as indigenous medicine or folk medicine) comprises medical aspects of traditional knowledge that developed over generations within the folk beliefs of various societies, including indigenous peoples, before the ...

for treating heart failure.

References

External links

* {{Cite news, first=Harriet, last=Hall, author-link=Harriet Hall, url=https://sciencebasedmedicine.org/forskolin-here-we-go-again/, title=Forskolin: Here We Go Again, date=2014-06-03, work=Science-Based Medicine, access-date=2017-04-12, language=en-US Diterpenes Vinyl compounds Ketones Triols Acetate esters Enzyme activators