Nepetalactone is a name for multiple iridoidanalogstereoisomers. Nepetalactones are produced by Nepeta cataria (catnip) and many other plants belonging to the genus Nepeta, in which they protect these plants from herbivorous insects by functioning as insect repellents. They are also produced by many aphids, in which they are sex pheromones.[1] 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 lions and jaguars.[2] In 1941, the research group of Samuel M. McElvain was the first to determine the structures of nepetalactones and several related compounds.[3][4]
(cis,trans)-Nepetalactone is a colorless oil.[5] Its boiling point is 71°C at 0.05mmHg. At 25°C, its density is 1.0663g/mL and refractive index 1.4859.[6]
Natural occurrence
Plants belonging to the Nepeta genus produce 4 different nepetalactone stereoisomers: (cis,cis)-, (cis,trans)-, (trans,cis)- and (trans,trans)-nepetalactone.[clarification needed] Their relative occurrence varies among plant species.[7] 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.[8]
Nepetalactones are also produced by many aphids, in which they function as sex pheromones. The most common isomer in aphids is (cis,trans)-nepetalactone. Aphids also commonly produce a structurally related (1R,4aS,7S,7aR)-nepetalactol, which is also an aphid sex pheromone. Relative concentrations of these two compounds varies among aphid species.[9]
Biosynthesis
Nepetalactone is a bicyclic monoterpene produced through the terpenoid pathway in the genus Nepeta using its starting compound, geranyl pyrophosphate (GPP).[10] There are three isomers of nepetalactone and it is suggested their stereochemistry is produced using different enzymes. Geranyl pyrophosphate undergoes hydrolysis and several oxidations to form 8-oxogeranial which can undergo a canonical activation–cyclation step in iridoid biosynthesis. Uncanonically, 8-oxogeranial will be reduced to create an 8-oxocitronellyl enol intermediate. Through a Diels–Alder reaction with a group of cyclases known as nepetalactone-related short-chain dehydrogenase enzymes (NEPS), the different stereoisomers of nepetalactone are biosynthesized.[11]
The process starts with geraniol synthase (GES) hydrolyzing GPP to form geraniol which is oxidized into 8-hydrogeraniol by geraniol-8-hydroxylase (G8H) (scheme 1).[12] 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 to form the intermediate 8-oxocitronellyl enol (scheme 2). This intermediate leads to cyclization by a gene cluster which utilizes ISY and major latex-protein-like genes (MLPL) or NEPS homologs.[1] 8-oxocitronellyl enol 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 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 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.[1]
Nepetalactones affect domestic cats via nasal mucosa. Oral ingestion has no effects.[5] 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.[2]
The effects of nepetalactones begin quickly in domestic cats, and last for 5 to 15 minutes. Cats develop drug tolerance towards nepetalactones after exposure. The tolerance lasts for a few hours.[5]
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-like posture, decrease vocalization or decrease movement. The effects of nepetalactones are similar in other Felidae.[2]
Mechanism of action
Felidae olfactory receptor exposure to nepetalactones or nepetalactols induces β-endorphin secretion in the blood; this endorphin release in turn activates μ-opioid receptors as an agonist, thus working in a similar manner as morphine or other opioids.[5]Naloxone, a μ-opioid receptor antagonist, is known to block the effects of nepetalactones and nepetalactols in domestic cats, which supports this endorphin related mechanism of action.[2][5] Repeated exposure to nepetalactones or nepetalactols does not induce opioid withdrawals in Felidae, probably because endogenous β-endorphin secretion is controlled.[5] (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.[8]
Evolutionary reasons for the effects
Felidae react to plants that contain nepetalactones by licking them and rubbing them in their fur.[5] Nepetalactones and nepetalactols repel some disease-causing insects. For example, nepetalactols are able to repel Aedes albopictus.[5][1] 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 select for the behavior of rubbing of natural insect repellent. This was proposed to be the reason for this widely preserved behavioral trait in Felidae in a paper published in 2021.[5]
↑ McElvain SM, Bright RD, Johnson PR (1941). "The constituents of the volatile oil of catnip. I. Nepetalic acid, nepetalactone and related compounds". Journal of the American Chemical Society. 63 (6): 1558–1563. doi:10.1021/ja01851a019.
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 space. This contrasts with structural isomers, which share the same molecular formula, but the bond connections or their order differs. By definition, molecules that are stereoisomers of each other represent the same structural isomer.
Valerian is a perennial flowering plant native to Europe and Asia. In the summer when the mature plant may have a height of 1.5 metres, it bears sweetly scented pink or white flowers that attract many fly species, especially hoverflies of the genus Eristalis. It is consumed as food by the larvae of some Lepidoptera species, including the grey pug.
In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic form. This creates a 1:1 molar ratio of enantiomers and is referred to as a racemic mixture. Plus and minus forms are called Dextrorotation and levorotation. The D and L enantiomers are present in equal quantities, the resulting sample is described as a racemic mixture or a racemate. Racemization can proceed through a number of different mechanisms, and it has particular significance in pharmacology as different enantiomers may have different pharmaceutical effects.
In stereochemistry, diastereomers are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have different configurations at one or more of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereoisomers differ from each other at only one stereocenter, they are epimers. Each stereocenter gives rise to two different configurations and thus typically increases the number of stereoisomers by a factor of two.
In biochemistry, isomerases are a general class of enzymes that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which bonds are broken and formed. The general form of such a reaction is as follows:
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 of a pre-existing one. The selectivity arises from differences in steric and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since the activation energy difference between the two pathways is finite: both products are at least possible and merely differ in amount. However, in favorable cases, the minor stereoisomer may not be detectable by the analytic methods used.
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 root and silver vine, as well as several types of insects in the larval and imaginal stages. Actinidine is a cat attractant, with effects like those of nepetalactone, the active compound found in catnip.
Pulegone is a naturally occurring organic compound obtained from the essential oils of a variety of plants such as Nepeta cataria (catnip), Mentha piperita, and pennyroyal. It is classified as a monoterpene.
The term farnesene refers to a set of six closely related chemical compounds which all are sesquiterpenes. α-Farnesene and β-farnesene are isomers, differing by the location of one double bond. α-Farnesene is 3,7,11-trimethyl-1,3,6,10-dodecatetraene and β-farnesene is 7,11-dimethyl-3-methylene-1,6,10-dodecatriene. The alpha form can exist as four stereoisomers that differ about the geometry of two of its three internal double bonds. The beta isomer exists as two stereoisomers about the geometry of its central double bond.
Schizonepeta is a genus of herbs. It should not be confused with the true catnips of the genus Nepeta known for their euphoria-inducing effect on domestic cats.
(S)-3,5-Dihydroxyphenylglycine or DHPG is a potent agonist of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5.
A cat pheromone is a chemical molecule, or compound, that is used by cats and other felids for communication. These pheromones are produced and detected specifically by the body systems of cats and evoke certain behavioural responses.
Prenyltransferases (PTs) are a class of enzymes that transfer allylic prenyl groups to acceptor molecules. Prenyl transferases commonly refer to isoprenyl diphosphate syntheses (IPPSs). Prenyltransferases are a functional category and include several enzyme groups that are evolutionarily independent.
Chrysanthemic acid is an organic compound that is related to a variety of natural and synthetic insecticides. It is related to the pyrethrin I and II, as well as the pyrethroids. One of the four stereoisomers, (1R,3R)- or (+)-trans-chrysanthemic acid (pictured), is the acid part of the ester pyrethrin I, which occurs naturally in the seed cases of Chrysanthemum cinerariaefolium. Many synthetic pyrethroids, for example the allethrins, are esters of all four stereoisomers. Staudinger and Ružička named chrysanthemic acid in 1924.
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 naturalized in northern Europe, New Zealand, and North America. The common name catmint can also refer to the genus as a whole.
Actinidia polygama is a species of kiwifruit in the family Actinidiaceae. It grows in the mountainous areas of Korea, Japan and China at elevations between 500 and 1,900 metres.
Iridomyrmecin is a defensive chemical, classified as an iridoid, isolated from ants of the genus Iridomyrmex. It has also evolved into a sex pheromone in wasps such as Leptopilina, with host species using the smell of iridomyrmecin as a way of detecting the presence of the parasitoid wasps. Iridomyrmecin is also found in a variety of plants including Actinidia polygama.
8-Oxogeranial is a chemical substance, that is a monoterpene. The terpenoid is produced by 8-hydroxygeraniol dehydrogenase which uses 8-hydroxygeraniol as its substrate. 8-Oxogeranial is itself a substrate for iridoid synthase which synthesizes cis–trans-iridodial and cis–trans-nepetalactol.
Nepetalactol is an iridoid. It is produced from 8-oxogeranial by the enzyme iridoid synthase. Nepetalactol is a substrate for the enzyme iridoid oxidase (IO) which produces 7-deoxyloganetic acid. It has been identified in Actinidia polygama as a major cat attractant, and a mosquito repellent. The fact that mosquitos bite cats with nepetalactol on their fur less often may explain why cats are attracted to silver vine in the first place.
Cannabidiol-dimethylheptyl (CBD-DMH or DMH-CBD) is a synthetic homologue of cannabidiol where the pentyl chain has been replaced by a dimethylheptyl chain. Several isomers of this compound are known. The most commonly used isomer in research is (−)-CBD-DMH, which has the same stereochemistry as natural cannabidiol, and a 1,1-dimethylheptyl side chain. This compound is not psychoactive and acts primarily as an anandamide reuptake inhibitor, but is more potent than cannabidiol as an anticonvulsant and has around the same potency as an antiinflammatory. Unexpectedly the “unnatural” enantiomer (+)-CBD-DMH, which has reversed stereochemistry from cannabidiol, was found to be a directly acting cannabinoid receptor agonist with a Ki of 17.4nM at CB1 and 211nM at CB2, and produces typical cannabinoid effects in animal studies, as does its 7-OH derivative.
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