Caleicine is a unique

sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many combinations. Biochemical modifications s ...

compound found exclusively in ''

Calea ternifolia ''Calea ternifolia'' ( syn. ''Calea zacatechichi'') is a species of flowering plant in the aster family, Asteraceae. It is native to Mexico and Central America. Its English language common names include bitter-grass, Mexican calea, and dream herb ...

'', a Mexican flowering plant known for its potential psychoactive properties. This compound has garnered interest in the field of

ethnopharmacology Ethnomedicine is a study or comparison of the traditional medicine based on bioactive compounds in plants and animals and practiced by various ethnic groups, especially those with little access to western medicines, e.g., indigenous peoples. The ...

and

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...

chemistry due to its putative role as a prodrug of

eugenol Eugenol is an allyl chain-substituted guaiacol, a member of the allylbenzene class of chemical compounds. It is a colorless to pale yellow, aromatic oily liquid extracted from certain essential oils especially from clove, nutmeg, cinnamon, ...

, a potent GABA positive modulator. Caleicine is the ''p''-Coumaric ester of junenol and has no

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

moiety making it distinctly unique from the other

sesquiterpene lactone Sesquiterpene lactones (SLs) are a class of sesquiterpenoids that contain a lactone ring. They are most often found in plants of the family Asteraceae (daisies, asters). Other plant families with SLs are Umbelliferae (celery, parsley, carrots) ...

s in

Chemistry

Caleicine is a sesquiterpene that has a

phenylpropanoid The phenylpropanoids are a diverse family of organic compounds that are biosynthesized by plants from the amino acids phenylalanine and tyrosine in the shikimic acid pathway. Their name is derived from the six-carbon, aromatic phenyl group and ...

moiety bonded to junenol In an investigation,

lab mice The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory animal sources for these mice are usually of the species ''Mus musculus''. They a ...

were administered with an aqueous solution of ''Calea ternifolia'' in doses of 200, 400 and 800 mg and made to undergo a

forced swim test ''Forced'' is a single-player and co-op action role-playing game developed by BetaDwarf, released in October 2013 for Windows, OS X and Linux through the Steam platform as well as Wii U. It is about gladiators fighting for their freedom in a fant ...

. Under dosages of 400 and 800 mg, the mice showed depressive like effects.

Theorised Mechanism of action

The mechanisms of ''Calea ternifolia'' induced

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

are not well understood, however, caleicine could play a role due to its potential metabolism. Caleicine contains ''p''-Coumaric acid. In the body, ''p''-Coumaric acid is biosynthesised into many lignols and phenylpropanoids including

. Eugenol acts as a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

of the

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

which is common amongst

oneirogen An oneirogen, from the Greek ὄνειρος ''óneiros'' meaning "dream" and ''gen'' "to create", is a substance that induces a dream-like state of consciousness. Oneirogens function by altering neural processing in a way that shifts the brain ...

s. In addition, eugenol inhibits both MAO-A and MAO-B, inhibiting the metabolism of

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

and

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. Eugenol is one of many potential metabolites of caleicine, and the mechanisms of both caleicine (specifically) and the herb ''Calea ternifolia'' (more broadly) are poorly understood. Caleicine is a unique sesquiterpene compound found only in ''Calea ternifolia'' and is one of many

GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter gamma-aminobutyric acid (GABA). For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic ...

compounds found in the plant and acts as a prodrug to the known bioactive and potent eugenol. Caleicine is a strong candidate to be responsible the effects of ''Calea ternifolia'' as the GABA modulation eugenol exhibits are the same that of ''Calea ternifolia''. Negative side effects associated with ''Calea ternifolia'' include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

and delirium based hallucinations, which are similar to those are similar to those associated with eugenol. GABA positive allosteric site modulation is found in many sedative substances such as

methaqualone Methaqualone is a hypnotic sedative. It was sold under the brand names Quaalude ( ) and Sopor among others, which contained 300 mg of methaqualone, and sold as a combination drug under the brand name Mandrax, which contained 250 mg me ...

propofol Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was approved under the brand name Diprivan. Nu ...

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

, and

zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...

. The properties of GABA positive modulating substances typically are

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

ic,

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

euphoriant Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...

, and

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

effects.

References

{{reflist Sesquiterpenes Esters 4-Hydroxyphenyl compounds Decalins Isopropyl compounds

Chemistry

Theorised Mechanism of action

See also

References