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, mos ...

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use 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 in ...

. Nepetalactones are produced by ''Nepeta cataria'' (

catnip ''Nepeta cataria'', commonly known as catnip, catswort, catwort, and catmint, is a species of the genus '' Nepeta'' in the family Lamiaceae, native to southern and eastern Europe, the Middle East, Central Asia, and parts of China. It is widely ...

) and many other plants belonging to the genus ''

Nepeta ''Nepeta'' is a genus of flowering plants in the family Lamiaceae. The genus name is reportedly in reference to Nepete, an ancient Etruscan city.

'', in which they protect these plants from herbivorous insects by functioning as

insect repellent An insect repellent (also commonly called "bug spray") is a substance applied to skin, clothing, or other surfaces to discourage insects (and arthropods in general) from landing or climbing on that surface. Insect repellents help prevent and cont ...

s. They are also produced by many

aphid Aphids are small sap-sucking insects and members of the superfamily Aphidoidea. Common names include greenfly and blackfly, although individuals within a species can vary widely in color. The group includes the fluffy white woolly aphids. A t ...

s, in which they are

sex pheromones Sex pheromones are pheromones released by an organism to attract an individual of the same species, encourage them to mate with them, or perform some other function closely related with sexual reproduction. Sex pheromones specifically focus on ind ...

. 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 Felidae () is the family of mammals in the order Carnivora colloquially referred to as cats, and constitutes a clade. A member of this family is also called a felid (). The term "cat" refers both to felids in general and specifically to the dom ...

, especially in

lion The lion (''Panthera leo'') is a large Felidae, cat of the genus ''Panthera'' native to Africa and India. It has a muscular, broad-chested body; short, rounded head; round ears; and a hairy tuft at the end of its tail. It is sexually dimorphi ...

s and

jaguar The jaguar (''Panthera onca'') is a large cat species and the only living member of the genus '' Panthera'' native to the Americas. With a body length of up to and a weight of up to , it is the largest cat species in the Americas and the th ...

s. In 1941, the research group of

Samuel M. McElvain Samuel Marion McElvain (December 9, 1897 – April 11, 1973) was an American organic and synthetic chemist who spent his research career on the faculty of the University of Wisconsin. Academic career McElvain studied first at Washington Uni ...

was the first to determine the structures of nepetalactones and several related compounds.

Structure and properties

Nepetalactone has three

chiral centers In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...

, two at the

fusion Fusion, or synthesis, is the process of combining two or more distinct entities into a new whole. Fusion may also refer to: Science and technology Physics *Nuclear fusion, multiple atomic nuclei combining to form one or more different atomic nucl ...

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 . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

attaches to the

cyclopentane Cyclopentane (also called C pentane) is a highly flammable alicyclic hydrocarbon with chemical formula C5H10 and CAS number 287-92-3, consisting of a ring of five carbon atoms each bonded with two hydrogen atoms above and below the plane. It occur ...

ring. Thus, it has eight (2³)

. 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, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...

on the cyclopentane. (''cis'',''trans'')-Nepetalactone is a colorless oil. Its boiling point is 71 °C at 0.05 mmHg. 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 a dimensionless number that gives the indication of the light bending ability of that medium. The refractive index determines how much the path of light is bent, or ...

1.4859.

Natural occurrence

Plants belonging to the ''

Nepeta ''Nepeta'' is a genus of flowering plants in the family Lamiaceae. The genus name is reportedly in reference to Nepete, an ancient 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 Actinidine is an iridoid produced in nature by a wide variety of plants and animals. It was the first cyclopentanoid monoterpene alkaloid to be discovered. It is one of several compounds that may be extracted from the valerian (''Valeriana off ...

, which occurs in it in higher concentrations. Nepetalactones are also produced by many

s, in which they function as

. 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 funct ...

produced through the

terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...

pathway in the genus ''

Nepeta ''Nepeta'' is a genus of flowering plants in the family Lamiaceae. The genus name is reportedly in reference to Nepete, an ancient 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 natural products. Occurrence GPP is an intermediate in the isoprenoid ...

(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 natural products. Occurrence GPP is an intermediate in the isoprenoid ...

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

biosynthesis. Uncanonically, 8-oxogeranial will be reduced to create an 8-oxocitronellyl

enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The te ...

intermediate. Through a

Diels–Alder reaction In organic chemistry, the Diels–Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene derivative. It is the prototypical example of a peric ...

with a group of

cyclase A cyclase is an enzyme, almost always a lyase, that catalyzes a chemical reaction to form a cyclic compound. Important cyclase enzymes include: * Adenylyl cyclase, which forms cyclic AMP from adenosine triphosphate (EC 4.6.1.1) ** ADCY1 ** ADCY2 ...

s 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, palmarosa oil. It is a colorless oil, although commercial samples can appear yellow. It has low solubility in w ...

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 NAD ...

to form the intermediate 8-oxocitronellyl

(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

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

cyclizing into (''cis'',''cis'')-nepetalactol by NEPS3 and oxidation by NEPS1 or NEPS5 and NAD+ to yield (''cis'',''cis'')-nepetalactone (scheme 4). 8-Oxocitronellyl

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. Nepetalactone Biosynthesis

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 Neutering, from the Latin ''neuter'' ('of neither sex'), is the removal of an animal's reproductive organ, either all of it or a considerably large part. The male-specific term is castration, while spaying is usually reserved for female animals. C ...

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 Africa and India. It has a muscular, broad-chested body; short, rounded head; round ears; and a hairy tuft at the end of its tail. It is sexually dimorphic; adult ...

'') and jaguars (''

Panthera onca The jaguar (''Panthera onca'') is a large cat species and the only living member of the genus '' Panthera'' native to the Americas. With a body length of up to and a weight of up to , it is the largest cat species in the Americas and the th ...

'') are sensitive to nepetalactones. Their effects can last in them for up to 60 minutes. They also affect leopards (''

Panthera pardus The leopard (''Panthera pardus'') is one of the five extant species in the genus ''Panthera'', a member of the cat family, Felidae. It occurs in a wide range in sub-Saharan Africa, in some parts of Western and Central Asia, Southern Russia, an ...

''). They do not affect tigers (''

Panthera tigris The tiger (''Panthera tigris'') is the largest living cat species and a member of the genus '' Panthera''. It is most recognisable for its dark vertical stripes on orange fur with a white underside. An apex predator, it primarily preys on u ...

''), bobcats (''

Lynx rufus The bobcat (''Lynx rufus''), also known as the red lynx, is a medium-sized cat native to North America. It ranges from southern Canada through most of the contiguous United States to Oaxaca in Mexico. It is listed as Least Concern on the I ...

''), cougars (''

Puma concolor The cougar (''Puma concolor'') is a large cat native to the Americas. Its range spans from the Canadian Yukon to the southern Andes in South America and is the most widespread of any large wild terrestrial mammal in the Western Hemisphere ...

'') 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 ( , grc, σφίγξ , Boeotian: , plural sphinxes or sphinges) is a mythical creature with the head of a human, the body of a lion, and the wings of a falcon. In Greek tradition, the sphinx has the head of a woman, the haunches of ...

-like posture, decrease vocalization or decrease movement. The effects of nepetalactones are similar in other

Felidae Felidae () is the family of mammals in the order Carnivora colloquially referred to as cats, and constitutes a clade. A member of this family is also called a felid (). The term "cat" refers both to felids in general and specifically to the ...

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 ri ...

exposure to nepetalactones or nepetalactols induces

β-endorphin ''beta''-Endorphin (β-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced ...

secretion to blood. This endorphin activates

µ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalin An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are ...

s as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

, thus working in a similar manner as

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...

or other

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...

Naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin within ...

, 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 rece ...

, 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 withdrawal Opioid withdrawal is a set of symptoms (a syndrome) arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, ...

s 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'' (''Stegomyia albopicta''), from the mosquito (Culicidae) family, also known as the (Asian) tiger mosquito or forest mosquito, is a mosquito native to the tropical and subtropical areas of Southeast Asia. In the past few ce ...

''. 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 Any cause that reduces or increases reproductive success in a portion of a population potentially exerts evolutionary pressure, selective pressure or selection pressure, driving natural selection. It is a quantitative description of the amount of ...

select for the behavior of rubbing of natural

. 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 Cyclopentanes