Salsolinol
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Salsolinol is a
tetrahydroisoquinoline Tetrahydroisoquinoline (TIQ or THIQ), also known as AMPH-CR, is an organic compound with the chemical formula C9H11N. Classified as a secondary amine, it is derived from isoquinoline by hydrogenation. It is a colorless viscous liquid that is mis ...
derived from
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 ...
which plays a role in neurotransmission and is a
dopaminergic neurotoxin A monoamine neurotoxin, or monoaminergic neurotoxin, is a drug that selectively damages or destroys monoaminergic neurons. Monoaminergic neurons are neurons that signal via stimulation by monoamine neurotransmitters including serotonin, dopamine ...
. It has been linked to dopamine-related disorders including
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
and
alcohol use disorder Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...
. It is both synthesized in the human body and ingested in several common dietary sources.


Chemistry and structure

Salsolinol is a
catechol Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amounts. It ...
isoquinoline Isoquinoline is an individual chemical specimen - a heterocyclic aromatic organic compound - as well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". It is a struc ...
which is a yellow solid at room temperature. Salsolinol, as a
chiral Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is dist ...
molecule, comes in two
enantiomers In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
: (''R'')-salsolinol and (''S'')-salsolinol. The two may have different biological effects. The
racemate In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...
can be synthesized via a Pictet-Spengler reaction. A chemoenzymatic,
enantioselective In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation o ...
synthesis of the (''R'')-enantiomer has also been reported. Salsolinol has been used as a starting material to prepare some
tetrahydroisoquinoline Tetrahydroisoquinoline (TIQ or THIQ), also known as AMPH-CR, is an organic compound with the chemical formula C9H11N. Classified as a secondary amine, it is derived from isoquinoline by hydrogenation. It is a colorless viscous liquid that is mis ...
-based prospective drugs.


Biochemistry


Natural occurrence

Salsolinol is found in several edible plants, most prominently bananas and cocoa products as well as beer. Other plants, including
black cohosh ''Actaea racemosa'', the black cohosh, black bugbane, black snakeroot, rattle-top, or fairy candle ( syn. ''Cimicifuga racemosa''), is a species of flowering plant of the family Ranunculaceae. It is native to eastern North America from the ext ...
, which is used in many herbal remedies, also contain salsolinol.


Biosynthesis

Salsolinol is endogenously synthesized by multiple routes, although its origin in the human body remains controversial. There are two main routes for its production: one which is through a non-enantiospecific Pictet-Spengler reaction of dopamine and
acetaldehyde Acetaldehyde (IUPAC systematic name ethanal) is an organic compound, organic chemical compound with the chemical formula, formula , sometimes abbreviated as . It is a colorless liquid or gas, boiling near room temperature. It is one of the most ...
, and one which is mediated by the enzyme salsolinol synthase. Salsolinol synthase exclusively produces the (''R'')-enantiomer of salsolinol. It has been speculated that salsolinol may also arise from salsolinol-1-carboxylic acid, which is formed by the reaction of dopamine and
pyruvic acid Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an metabolic intermediate, intermediate in several m ...
. This transformation would occur via a proposed enzymatic pathway that has not been elucidated yet.


Metabolism

Salsolinol is metabolized by an
N-methyltransferase N-methyltransferase may refer to: *(RS)-1-benzyl-1,2,3,4-tetrahydroisoquinoline N-methyltransferase * 3-hydroxy-16-methoxy-2,3-dihydrotabersonine N-methyltransferase * Amine N-methyltransferase * Anthranilate N-methyltransferase * (cytochrome c)-ar ...
enzyme into ''N''-methyl-(''R'')-salsolinol. This can then be converted by an amine oxidase into 1,2-dimethyl-6,7-dihydroxyisoquinolinium (DMDHIQ+). It can also be methylated to form its 7-methoxy and 6-methoxy versions by the enzyme
catechol-O-methyltransferase Catechol-''O''-methyltransferase (COMT; ) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol struct ...
(COMT). :


Role in the body


Neurotoxicity and neurotransmission

Salsolinol binds to several receptors associated with
dopaminergic pathways Dopaminergic pathways (dopamine pathways, dopaminergic projections) in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine contro ...
. It may be an
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the
μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
and of dopaminergic D1 and D3 receptors. Salsolinol itself also appears to be neurotoxic, the mechanism of which is not clear. Its metabolites, including ''N''-methyl-(''R'')-salsolinol, also exhibit neurotoxic effects.


Prolactin

Salsolinol has been shown to be involved in the secretion of
prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...
in the
pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
in lactating rats and lactating sheep. Administration of a solution of salsolinol was not shown to raise prolactin levels in human women.


Disease and disorders


Parkinson's disease

Salsolinol is detectable in the
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
(PD) patients and is involved in the pathogenesis of PD. It is known to exercise inhibitory effects on
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...
and to be toxic to dopaminergic neurons. A mechanism for the induction of Parkinson's by salsolinol is linked to its mediation of
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of ...
.


Alcohol intake and alcohol use disorders

The connection between salsolinol and alcohol intake remains controversial. An early hypothesis was that the synthesis of salsolinol in the human body was caused by ethanol consumption, because it was being made from dopamine and acetaldehyde (a metabolite of ethanol). Several studies in the 1970s and 80s would seem to corroborate this link. However, no consistent connection between ethanol intake and salsolinol levels were conclusively established. As of the 2020s, it is understood that the primary contributor to levels of salsolinol in blood plasma is dietary intake, not acute ethanol consumption. Part of the challenge in studying this is that salsolinol also is produced endogenously, and in all cases its levels are very low, making it difficult to detect and quantify with precision. Further confounding the issue, there is evidence that salsolinol may be implicated in alcohol use disorder and may play a role in increasing cravings for ethanol. (''R'')-Salsolinol stereospecifically induces behavioral sensitization and leads to excessive alcohol intake in rats.


See also

*
Substituted tetrahydroisoquinoline A substituted tetrahydroisoquinoline is a tetrahydroisoquinoline with one or more chemical substituents. Many simple tetrahydroisoquinoline alkaloids related to mescaline are known and occur naturally in cactus species such as peyote (''Lophophor ...
* Norsalsolinol *
6-Hydroxydopamine Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine, is a synthetic monoaminergic neurotoxin used by researchers to selectively destroy dopaminergic and noradrenergic neurons in the brain. The main use for ox ...
*
MPTP MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is an organic compound. It is classified as a tetrahydropyridine. It is of interest as a precursor to the monoaminergic neurotoxin MPP+, which causes permanent symptoms of Parkinson's dise ...
*
Rotenone Rotenone is an odorless, colorless, crystalline isoflavone. It occurs naturally in the seeds and stems of several plants, such as the jicama vine, and in the roots of several other members of the Fabaceae. It was the first-described member of the ...


References

{{Phenethylamines Catechols Dopamine Human pathological metabolites Monoaminergic neurotoxins Tetrahydroisoquinoline alkaloids