nepetalactone
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Nepetalactone is a name for multiple
iridoid Iridoids are a type of monoterpenoids in the general form of cyclopentanopyran, found in a wide variety of plants and some animals. They are biosynthetically derived from 8-oxogeranial. Iridoids are typically found in plants as glycosides, mo ...
analog
stereoisomers In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...
. Nepetalactones are produced by ''Nepeta cataria'' (
catnip ''Nepeta cataria'', commonly known as catnip and catmint, is a species of the genus ''Nepeta'' in the mint family, native plant, native to southern and eastern Europe, northern parts of the Middle East, and Central Asia. It is widely naturalis ...
) and many other plants belonging to the genus ''
Nepeta ''Nepeta'' is a genus of flowering plants in the family (biology), family Lamiaceae. The genus name, from Latin (“catnip”), is reportedly in reference to Nepi, Nepete, an ancient Etruscan cities, Etruscan city.
'', in which they protect these plants from herbivorous insects by functioning as
insect repellent An insect repellent (also commonly called "bug spray" or "bug deterrent") is a substance applied to the skin, clothing, or other surfaces to discourage insects (and arthropods in general) from landing or climbing on that surface. Insect repellent ...
s. They are also produced by many
aphid Aphids are small sap-sucking insects in the Taxonomic rank, family Aphididae. Common names include greenfly and blackfly, although individuals within a species can vary widely in color. The group includes the fluffy white Eriosomatinae, woolly ...
s, in which they are sex pheromones. Nepetalactones are cat attractants, and cause the behavioral effects that catnip induces in domestic cats. However, they affect visibly only about two thirds of adult cats. They produce similar behavioral effects in many other felids, especially in
lion The lion (''Panthera leo'') is a large Felidae, cat of the genus ''Panthera'', native to Sub-Saharan Africa and India. It has a muscular, broad-chested body (biology), body; a short, rounded head; round ears; and a dark, hairy tuft at the ...
s and
jaguar The jaguar (''Panthera onca'') is a large felidae, cat species and the only extant taxon, living member of the genus ''Panthera'' that is native to the Americas. With a body length of up to and a weight of up to , it is the biggest cat spe ...
s. In 1941, the research group of Samuel M. McElvain was the first to determine the structures of nepetalactones and several related compounds.


Structure and properties

Nepetalactone has three chiral centers, two at the fusion of the two rings, and one where the
methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...
attaches to the
cyclopentane Cyclopentane (also called C pentane) is a highly flammable alicyclic compound, alicyclic hydrocarbon with chemical formula C5H10, C5H10 and CAS number 287-92-3, consisting of a ring of five carbon atoms each bonded with two hydrogen atoms above and ...
ring. Thus, it has eight (23)
stereoisomers In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...
. The terms ''cis'' and ''trans'' are used to refer to the relative stereochemistry at the ring fusion, and also to the methyl group as compared to the
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 ...
on the cyclopentane. (''cis'',''trans'')-Nepetalactone is a colorless oil. Its boiling point is 71 °C at 0.05 
mmHg A millimetre of mercury is a manometric unit of pressure, formerly defined as the extra pressure generated by a column of mercury one millimetre high. Currently, it is defined as exactly , or approximately 1 torr =  atmosphere = &nb ...
. At 25 °C, its density is 1.0663 g/mL and
refractive index In optics, the refractive index (or refraction index) of an optical medium is the ratio of the apparent speed of light in the air or vacuum to the speed in the medium. The refractive index determines how much the path of light is bent, or refrac ...
1.4859.


Natural occurrence

Plants belonging to the ''
Nepeta ''Nepeta'' is a genus of flowering plants in the family (biology), family Lamiaceae. The genus name, from Latin (“catnip”), is reportedly in reference to Nepi, Nepete, an ancient Etruscan cities, Etruscan city.
'' genus produce 4 different nepetalactone stereoisomers: (''cis'',''cis'')-, (''cis'',''trans'')-, (''trans'',''cis'')- and (''trans'',''trans'')-nepetalactone. Their relative occurrence varies among plant species. Small amounts of (''cis'',''trans'')- and (''trans'',''cis'')-nepetalactone also occur in the wood of '' Lonicera tatarica'', but its cat attractant effects are assumed to be caused by actinidine, which occurs in it in higher concentrations. Nepetalactones are also produced by many
aphid Aphids are small sap-sucking insects in the Taxonomic rank, family Aphididae. Common names include greenfly and blackfly, although individuals within a species can vary widely in color. The group includes the fluffy white Eriosomatinae, woolly ...
s, in which they function as sex pheromones. The most common isomer in aphids is (''cis'',''trans'')-nepetalactone. Aphids also commonly produce a structurally related (1''R'',4a''S'',7''S'',7a''R'')- nepetalactol, which is also an aphid sex pheromone. Relative concentrations of these two compounds varies among aphid species.


Biosynthesis

Nepetalactone is a bicyclic
monoterpene Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings (monocyclic and bicyclic). Modified terpenes, such as those containing oxygen func ...
produced through the
terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic compound, organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeabl ...
pathway in the genus ''
Nepeta ''Nepeta'' is a genus of flowering plants in the family (biology), family Lamiaceae. The genus name, from Latin (“catnip”), is reportedly in reference to Nepi, Nepete, an ancient Etruscan cities, Etruscan city.
'' using its starting compound,
geranyl pyrophosphate Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many thousands of natural product, natural products. Occurrence GPP is an int ...
(GPP). There are three isomers of nepetalactone and it is suggested their stereochemistry is produced using different enzymes.
Geranyl pyrophosphate Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many thousands of natural product, natural products. Occurrence GPP is an int ...
undergoes
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
and several oxidations to form 8-oxogeranial which can undergo a canonical activation–cyclation step in
iridoid Iridoids are a type of monoterpenoids in the general form of cyclopentanopyran, found in a wide variety of plants and some animals. They are biosynthetically derived from 8-oxogeranial. Iridoids are typically found in plants as glycosides, mo ...
biosynthesis. Uncanonically, 8-oxogeranial will be reduced to create an 8-oxocitronellyl
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
intermediate. Through a
Diels–Alder reaction In organic chemistry, the Diels–Alder reaction is a chemical reaction between a Conjugated system, conjugated diene and a substituted alkene, commonly termed the Diels–Alder reaction#The dienophile, dienophile, to form a substituted cyclohexe ...
with a group of cyclases known as nepetalactone-related short-chain dehydrogenase enzymes (NEPS), the different stereoisomers of nepetalactone are biosynthesized. The process starts with geraniol synthase (GES) hydrolyzing GPP to form
geraniol Geraniol is a monoterpenoid and an alcohol. It is the primary component of citronella oil and is a primary component of rose oil and palmarosa oil. It is a colorless oil, although commercial samples can appear yellow. It has low solubility i ...
which is oxidized into 8-hydrogeraniol by geraniol-8-hydroxylase (G8H) (scheme 1). Geraniol-8-hydroxylase is further oxidized by 8-hydroxygeraniol oxidoreductase (8OG) to produce 8-oxo-geranial which is reduced by iridoid synthase (ISY) and
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...
to form the intermediate 8-oxocitronellyl
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
(scheme 2). This intermediate leads to cyclization by a gene cluster which utilizes ISY and major latex-protein-like genes (MLPL) or NEPS homologs. 8-oxocitronellyl
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
is cyclized into (''cis'',''trans'')-nepetalactol by MLPL, NEPS1, or NEPS2 and then oxidized by NEPS5 and the cofactor NAD+ to yield (''cis'',''trans'')-nepetalactone (scheme 3). The process can be repeated with 8-oxocitronellyl
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
cyclizing into (''cis'',''cis'')-nepetalactol by NEPS3 and oxidation by NEPS1 or NEPS5 and NAD+ to yield (''cis'',''cis'')-nepetalactone (scheme 4). 8-Oxocitronellyl
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
can also be cyclized into (''trans'',''cis'')-nepetalactol by NEPS4 and then oxidized by NEPS1 into (''trans'',''cis'')-nepetalactone (scheme 5). It is suggested that the lack of the NEPS1 leads to decay and formation of (''trans'',''cis'')- iridodial.


Effects in felines


Duration and efficacy variation

Nepetalactones affect domestic cats via
nasal mucosa The nasal mucosa lines the nasal cavity. It is part of the respiratory mucosa, the mucous membrane lining the respiratory tract. The nasal mucosa is intimately adherent to the periosteum or perichondrium of the nasal conchae. It is continuous w ...
. Oral ingestion has no effects. They induce noticeable behavioral effects in about two thirds of adult cats. However, all cats are probably affected by them, but the effects in one third of adult cats are less visible. Nepetalactones do not noticeably affect kittens that are less than three months old. Their effects also tend to be less pronounced in neutered cats in comparison to non-neutered cats, but not significantly. The effects of nepetalactones begin quickly in domestic cats, and last for 5 to 15 minutes. Cats develop
drug tolerance Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further ...
towards nepetalactones after exposure. The tolerance lasts for a few hours. Lions (''
Panthera leo The lion (''Panthera leo'') is a large cat of the genus ''Panthera'', native to Sub-Saharan Africa and India. It has a muscular, broad-chested body; a short, rounded head; round ears; and a dark, hairy tuft at the tip of its tail. It is ...
'') and jaguars (''
Panthera onca The jaguar (''Panthera onca'') is a large cat species and the only living member of the genus ''Panthera'' that is native to the Americas. With a body length of up to and a weight of up to , it is the biggest cat species in the Americas a ...
'') are sensitive to nepetalactones. Their effects can last in them for up to 60 minutes. They also affect leopards ('' Panthera pardus''). Species exhibiting overall lesser to no sensitivity include tigers ('' Panthera tigris''), bobcats ('' Lynx rufus''), cougars (''
Puma concolor The cougar (''Puma concolor'') (, '' KOO-gər''), also called puma, mountain lion, catamount and panther is a large small cat native to the Americas. It inhabits North, Central and South America, making it the most widely distributed wil ...
'') or oncillas ('' Leopardus tigrinus'').{{Cite journal, display-authors=etal, vauthors=Resende LS, date=2011, title=Influence of cinnamon and catnip on the stereotypical pacing of oncilla cats (''Leopardus tigrinus'') in captivity, url=https://www.researchgate.net/publication/233194401, journal=Journal of Applied Animal Welfare Science, volume=14, issue=3, pages=247–254, doi=10.1080/10888705.2011.576981, pmid=22044295, s2cid=769991


Effects

Two thirds of adult domestic cats begin to lick, sniff, eat, scratch or roll over the nepetalactone source after being exposed to it. They may also begin pawing, shaking their heads, rubbing their cheeks, licking themselves or vocalizing. About one third of adult cats react more passively to nepetalactones, and may assume a
sphinx A sphinx ( ; , ; or sphinges ) is a mythical creature with the head of a human, the body of a lion, and the wings of an eagle. In Culture of Greece, Greek tradition, the sphinx is a treacherous and merciless being with the head of a woman, th ...
-like posture, decrease vocalization or decrease movement. The effects of nepetalactones are similar in other
Felidae Felidae ( ) is the Family (biology), family of mammals in the Order (biology), order Carnivora colloquially referred to as cats. A member of this family is also called a felid ( ). The 41 extant taxon, extant Felidae species exhibit the gre ...
.


Mechanism of action

Felidae
olfactory receptor Olfactory receptors (ORs), also known as odorant receptors, are chemoreceptors expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants (for example, compounds that have an odor) which give ...
exposure to nepetalactones or nepetalactols induces β-endorphin secretion in the blood; this endorphin release in turn activates
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 ...
s as 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 ...
, thus working in a similar manner as
morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
or other
opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
s.
Naloxone Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...
, a μ-opioid
receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
, is known to block the effects of nepetalactones and nepetalactols in domestic cats, which supports this endorphin related mechanism of action. Repeated exposure to nepetalactones or nepetalactols does not induce opioid withdrawals in Felidae, probably because endogenous β-endorphin secretion is controlled. (''cis'',''trans'')- and (''trans'',''cis'')-nepetalactones have both been shown to function as cat attractants in domestic cats in studies of poor quality. Both isomers occur in catnip for example, but the (''cis'',''trans'')-isomer is the major one.


Evolutionary reasons for the effects

Felidae react to plants that contain nepetalactones by licking them and rubbing them in their fur. Nepetalactones and nepetalactols repel some disease-causing insects. For example, nepetalactols are able to repel ''
Aedes albopictus ''Aedes albopictus'' (synonym (taxonomy), synonym ''Stegomyia albopicta''), from the mosquito (Culicidae) family (biology), family, also known as the (Asian) tiger mosquito or forest mosquito, is a mosquito native to the tropical and Subtropics ...
''. The cats typically hunt other animals by stalking them. This requires being still or slow movements, which allow insects to bite the cat more easily. This would make
evolutionary pressure Evolutionary pressure, selective pressure or selection pressure is exerted by factors that reduce or increase reproductive success in a portion of a population, driving natural selection. It is a quantitative description of the amount of change o ...
select for the behavior of rubbing of natural
insect repellent An insect repellent (also commonly called "bug spray" or "bug deterrent") is a substance applied to the skin, clothing, or other surfaces to discourage insects (and arthropods in general) from landing or climbing on that surface. Insect repellent ...
. This was proposed to be the reason for this widely preserved behavioral trait in Felidae in a paper published in 2021.


Sources

Cat attractants Pheromones Insect repellents Iridoids Lactones