Nepetalactone: Difference between revisions

| Watchedfields = changed

| verifiedrevid = 443389140

| ImageFile = Nepetalactone.svg

| ImageCaption = (''cis'',''trans'')-nepetalactone

| ImageFile2 = Nepetalactone-3D.png

| ImageCaption2 = (''cis'',''trans'')-nepetalactone

| IUPACName = 4,7-Dimethyl-5,6,7,7a-tetrahydrocyclopenta[''c'']pyran-1(4a''H'')-one

|Section1={{Chembox Identifiers

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo = 21651-62-7

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 7TM7PE24UW

| ChemSpiderID = 141747

| ChEBI = 7518

| PubChem = 161367

| SMILES = O=C1O\C=C(/[C@H]2CC[C@@H]([C@@H]12)C)C

| InChI = 1/C10H14O2/c1-6-3-4-8-7(2)5-12-10(11)9(6)8/h5-6,8-9H,3-4H2,1-2H3

|Section2={{Chembox Properties

| C=10 | H=14 | O=2

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|Section3={{Chembox Hazards

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'''Nepetalactone''' is a name for multiple [[iridoid]] [[Structural analog|analog]] [[stereoisomers]]. 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 repellent]]s. They are also produced by many [[aphid]]s, in which they are [[sex pheromones]].<ref name=d>{{Cite journal|display-authors=etal|vauthors=Lichman BR|date=2020|title=The evolutionary origins of the cat attractant nepetalactone in catnip|journal=Science Advances|volume=6|issue=20|pages=eaba0721 |doi=10.1126/sciadv.aba0721|pmc=7220310|pmid=32426505|bibcode=2020SciA....6..721L }}</ref> Nepetalactones are [[cat attractant]]s, 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 [[Felidae|felids]], especially in [[lion]]s and [[jaguar]]s.<ref name=b>{{Cite journal|display-authors=etal|vauthors=Espín-Iturbe LT|date=2017|title=Active and passive responses to catnip (''Nepeta cataria'') are affected by age, sex and early gonadectomy in male and female cats|url=http://www.sciencedirect.com/science/article/pii/S0376635717301766|journal=Behavioural Processes|volume=142|pages=110–115|doi=10.1016/j.beproc.2017.06.008|pmid=28698045|s2cid=37487390 }}</ref> In 1941, the research group of [[Samuel M. McElvain]] was the first to determine the structures of nepetalactones and several related compounds.<ref>{{Cite journal|vauthors=McElvain SM, Bright RD, Johnson PR|date=1941|title=The constituents of the volatile oil of catnip. I. Nepetalic acid, nepetalactone and related compounds|journal=Journal of the American Chemical Society|volume=63|issue=6|pages=1558–1563|doi=10.1021/ja01851a019}}</ref><ref>{{Cite journal|display-authors=etal|vauthors=Zimmermann N|date=2012|title=Stereoselective synthesis of ''trans''-fused iridoid lactones and their identification in the parasitoid wasp ''Alloxysta victrix'', Part I: Dihydronepetalactones|journal=Beilstein Journal of Organic Chemistry|volume=8|issue=1|pages=1246–1255|doi=10.3762/bjoc.8.140|pmc=3458745|pmid=23019455}}</ref>

==Structure and properties==

[[File:Nepetalactone isomers.svg|thumb|The relative stereochemistry of the nepetalactones]]

Nepetalactone has three [[chiral centers]], two at the [[fused-ring compound|fusion]] of the two rings, and one where the [[methyl group]] attaches to the [[cyclopentane]] ring. Thus, it has eight (2³) [[stereoisomers]]. The terms [[cis–trans isomerism|''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]] on the cyclopentane.{{huh|reason=When the fusion is ''trans'', do we compare the methyl to the carbonyl or the alkene?|date=January 2022}}

(''cis'',''trans'')-Nepetalactone is a colorless oil.<ref name=a>{{Cite journal|display-authors=etal|vauthors=Uenoyama R|date=2021|title=The characteristic response of domestic cats to plant iridoids allows them to gain chemical defense against mosquitoes|journal=Science Advances|volume=7|issue=4|pages=eabd9135 |doi=10.1126/sciadv.abd9135 |pmid=33523929 |pmc=7817105|bibcode=2021SciA....7.9135U |doi-access=free}}</ref> Its boiling point is 71&nbsp;°C at 0.05&nbsp;[[mmHg]]. At 25&nbsp;°C, its density is 1.0663&nbsp;g/mL and [[refractive index]] 1.4859.<ref>{{Cite book|title=CRC Handbook of Chemistry and Physics|vauthors=Haynes WM|publisher=CRC Press|year=2014|isbn=9781482208689|edition=95th|pages=408–409|chapter=3. Physical constants of organic compounds|display-authors=etal}}</ref>

==Natural occurrence==

Plants belonging to the ''[[Nepeta]]'' genus produce 4 different nepetalactone stereoisomers: (''cis'',''cis'')-, (''cis'',''trans'')-, (''trans'',''cis'')- and (''trans'',''trans'')-nepetalactone.{{clarify|reason=Is one of the stereocenters conserved (absolute R/S)?, given this is only 4 of 8 possibilities?|date=January 2022}} Their relative occurrence varies among plant species.<ref>{{Cite journal|display-authors=etal|vauthors=Sherden NH|date=2018|title=Identification of iridoid synthases from ''Nepeta'' species: Iridoid cyclization does not determine nepetalactone stereochemistry|journal=Phytochemistry|volume=145|pages=48–56|doi=10.1016/j.phytochem.2017.10.004|pmc=5739345|pmid=29091815|bibcode=2018PChem.145...48S }}</ref> 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.<ref name=e>{{Cite journal|display-authors=etal|vauthors=Bol S|date=2017|title=Responsiveness of cats (Felidae) to silver vine (''Actinidia polygama''), Tatarian honeysuckle (''Lonicera tatarica''), valerian (''Valeriana officinalis'') and catnip (''Nepeta cataria'')|journal=BMC Veterinary Research|volume=13|issue=1 |page=70 |doi=10.1186/s12917-017-0987-6|pmc=5356310|pmid=28302120 |doi-access=free }}</ref>

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* {{cite journal |vauthors=Autoren M |url=https://www.nature.com/articles/s41589-018-0185-2 |title="Uncoupled activation and cyclization in catmint reductive terpenoid biosynthesis" |journal=Nature Chemical Biology |year= 2019 |volume= 15 |pages= 71–79 }}

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Nepetalactones are also produced by many [[aphid]]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.<ref>{{Cite journal|vauthors=Döring TF|date=2014|title=How aphids find their host plants, and how they don't|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/aab.12142|journal=Annals of Applied Biology|volume=165|issue=1|pages=3–26|doi=10.1111/aab.12142|doi-access=free}}</ref>

==Biosynthesis==

Nepetalactone is a bicyclic [[monoterpene]] produced through the [[terpenoid]] pathway in the genus ''[[Nepeta]]'' using its starting compound, [[geranyl pyrophosphate]] (GPP).<ref>{{Cite journal|display-authors=etal|vauthors=Flores FG|date=2012|title=An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis|journal=Nature|volume=492|issue=7427 |pages=138–142|doi=10.1038/nature11692|pmid=23172143 |bibcode=2012Natur.492..138G |s2cid=4431685 }}</ref> 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 [[cyclase]]s known as nepetalactone-related short-chain dehydrogenase enzymes (NEPS), the different stereoisomers of nepetalactone are biosynthesized.<ref name>{{Cite journal|display-authors=etal|vauthors=Lichman BR|date=2020|title=The evolutionary origins of the cat attractant nepetalactone in catnip|journal=Science Advances|volume=6|issue=20|pages=eaba0721 |doi=10.1126/sciadv.aba0721|pmc=7220310|pmid=32426505|bibcode=2020SciA....6..721L }}</ref>

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).<ref>{{Cite journal|display-authors=etal|vauthors=Sherden NH|date=2018|title=Identification of iridoid synthases from ''Nepeta'' species: Iridoid cyclization does not determine nepetalactone stereochemistry|journal=Phytochemistry|volume=145|pages=48–56|doi=10.1016/j.phytochem.2017.10.004|pmc=5739345|pmid=29091815|bibcode=2018PChem.145...48S }}</ref> Geraniol-8-hydroxylase is further oxidized by 8-hydroxygeraniol oxidoreductase (8OG) to produce 8-oxo-geranial which is reduced by iridoid synthase (ISY) and [[Nicotinamide adenine dinucleotide phosphate|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.<ref name=d>{{Cite journal|display-authors=etal|vauthors=Lichman BR|date=2020|title=The evolutionary origins of the cat attractant nepetalactone in catnip|journal=Science Advances|volume=6|issue=20|pages=eaba0721 |doi=10.1126/sciadv.aba0721|pmc=7220310|pmid=32426505|bibcode=2020SciA....6..721L }}</ref> 8-oxocitronellyl [[enol]] is cyclized into (''cis'',''trans'')-nepetalactol by MLPL, NEPS1, or NEPS2 and then oxidized by NEPS5 and the cofactor [[Nicotinamide adenine dinucleotide|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 [[Nicotinamide adenine dinucleotide|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]].<ref name=d>{{Cite journal|display-authors=etal|vauthors=Lichman BR|date=2020|title=The evolutionary origins of the cat attractant nepetalactone in catnip|journal=Science Advances|volume=6|issue=20|pages=eaba0721 |doi=10.1126/sciadv.aba0721|pmc=7220310|pmid=32426505|bibcode=2020SciA....6..721L }}</ref>

[[File:Nepetalactone Biosynthesis.jpg|thumb|392 px|center|Nepetalactone Biosynthesis in ''[[Nepeta]]'']]

==Effects in felines==

===Duration and efficacy variation===

Nepetalactones affect [[domestic cats]] via [[nasal mucosa]]. Oral ingestion has no effects.<ref name=a/> 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.<ref name=b/>

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.<ref name=a/>

Lions (''[[Panthera leo]]'') and jaguars (''[[Panthera onca]]'') are sensitive to nepetalactones. Their effects can last in them for up to 60 minutes.<ref name=b/><ref name=c>{{Cite journal|display-authors=etal|vauthors=Hill JO|date=1976|title=Species-characteristic responses to catnip by undomesticated felids|url=https://link.springer.com/article/10.1007/BF00987747|journal=Journal of Chemical Ecology|volume=2|issue=2|pages=239–253|doi=10.1007/BF00987747|s2cid=24240498 }}</ref> They also affect leopards (''[[Panthera pardus]]''). Species exhibiting overall lesser to no sensitivity include tigers (''[[Panthera tigris]]''), bobcats (''[[Lynx rufus]]''),<ref name="e" /> cougars (''[[Puma concolor]]'')<ref name=c/> or oncillas (''[[Leopardus tigrinus]]'').<ref>{{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 }}</ref>

===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 [[Cat communication|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]].<ref name=b/>

===Mechanism of action===

Felidae [[olfactory receptor]] exposure to nepetalactones or [[nepetalactol]]s induces [[β-endorphin]] secretion in the blood; this endorphin release in turn activates [[µ-opioid receptor]]s as an [[agonist]], thus working in a similar manner as [[morphine]] or other [[opioid]]s.<ref name=a/> [[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.<ref name=b/><ref name=a/> Repeated exposure to nepetalactones or nepetalactols does not induce [[opioid withdrawal]]s in Felidae, probably because endogenous β-endorphin secretion is controlled.<ref name=a/> (''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.<ref name=e/>

===Evolutionary reasons for the effects===

Felidae react to plants that contain nepetalactones by licking them and rubbing them in their fur.<ref name=a/> Nepetalactones and nepetalactols repel some disease-causing insects. For example, nepetalactols are able to repel ''[[Aedes albopictus]]''.<ref name=a/><ref name=d/> 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.<ref name=a/>

==Sources==

[[Category:Insect repellents]]

[[Category:Lactones]]

[[Category:Cyclopentanes]]