Nepetalactone

(cis,trans)-nepetalactone

(cis,trans)-nepetalactone
Names
IUPAC name
4,7-Dimethyl-5,6,7,7a-tetrahydrocyclopenta[c]pyran-1(4aH)-one
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • InChI=1S/C10H14O2/c1-6-3-4-8-7(2)5-12-10(11)9(6)8/h5-6,8-9H,3-4H2,1-2H3/t6-,8+,9+/m0/s1 checkY
    Key: ZDKZHVNKFOXMND-NBEYISGCSA-N checkY
  • 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
  • Key: ZDKZHVNKFOXMND-NBEYISGCBC
  • O=C1O\C=C(/[C@H]2CC[C@@H]([C@@H]12)C)C
Properties
C10H14O2
Molar mass 166.220 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Infobox references

Nepetalactone is a name for multiple iridoid 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 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]

Structure and properties

The relative stereochemistry of the nepetalactones

Nepetalactone has three chiral centers, two at the 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 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.

(cis,trans)-Nepetalactone is a colorless oil.[5] Its boiling point is 71 °C at 0.05 mmHg. At 25 °C, its density is 1.0663 g/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. 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]

Nepetalactone Biosynthesis in Nepeta

Effects in felines

Duration and efficacy variation

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]

Lions (Panthera leo) and jaguars (Panthera onca) are sensitive to nepetalactones. Their effects can last in them for up to 60 minutes.[2][13] They also affect leopards (Panthera pardus). Species exhibiting overall lesser to no sensitivity include tigers (Panthera tigris), bobcats (Lynx rufus),[8] cougars (Puma concolor)[13] or oncillas (Leopardus tigrinus).[14]

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-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]

Sources

  1. 1 2 3 4 Lichman BR, et al. (2020). "The evolutionary origins of the cat attractant nepetalactone in catnip". Science Advances. 6 (20): eaba0721. Bibcode:2020SciA....6..721L. doi:10.1126/sciadv.aba0721. PMC 7220310. PMID 32426505.
  2. 1 2 3 4 5 Espín-Iturbe LT, et al. (2017). "Active and passive responses to catnip (Nepeta cataria) are affected by age, sex and early gonadectomy in male and female cats". Behavioural Processes. 142: 110–115. doi:10.1016/j.beproc.2017.06.008. PMID 28698045. S2CID 37487390.
  3. ↑ 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.
  4. ↑ Zimmermann N, et al. (2012). "Stereoselective synthesis of trans-fused iridoid lactones and their identification in the parasitoid wasp Alloxysta victrix, Part I: Dihydronepetalactones". Beilstein Journal of Organic Chemistry. 8 (1): 1246–1255. doi:10.3762/bjoc.8.140. PMC 3458745. PMID 23019455.
  5. 1 2 3 4 5 6 7 8 9 Uenoyama R, et al. (2021). "The characteristic response of domestic cats to plant iridoids allows them to gain chemical defense against mosquitoes". Science Advances. 7 (4): eabd9135. Bibcode:2021SciA....7.9135U. doi:10.1126/sciadv.abd9135. PMC 7817105. PMID 33523929.
  6. ↑ Haynes WM, et al. (2014). "3. Physical constants of organic compounds". CRC Handbook of Chemistry and Physics (95th ed.). CRC Press. pp. 408–409. ISBN 9781482208689.
  7. ↑ Sherden NH, et al. (2018). "Identification of iridoid synthases from Nepeta species: Iridoid cyclization does not determine nepetalactone stereochemistry". Phytochemistry. 145: 48–56. Bibcode:2018PChem.145...48S. doi:10.1016/j.phytochem.2017.10.004. PMC 5739345. PMID 29091815.
  8. 1 2 3 Bol S, et al. (2017). "Responsiveness of cats (Felidae) to silver vine (Actinidia polygama), Tatarian honeysuckle (Lonicera tatarica), valerian (Valeriana officinalis) and catnip (Nepeta cataria)". BMC Veterinary Research. 13 (1): 70. doi:10.1186/s12917-017-0987-6. PMC 5356310. PMID 28302120.
  9. ↑ Döring TF (2014). "How aphids find their host plants, and how they don't". Annals of Applied Biology. 165 (1): 3–26. doi:10.1111/aab.12142.
  10. ↑ Flores FG, et al. (2012). "An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis". Nature. 492 (7427): 138–142. Bibcode:2012Natur.492..138G. doi:10.1038/nature11692. PMID 23172143. S2CID 4431685.
  11. ↑ Lichman BR, et al. (2020). "The evolutionary origins of the cat attractant nepetalactone in catnip". Science Advances. 6 (20): eaba0721. Bibcode:2020SciA....6..721L. doi:10.1126/sciadv.aba0721. PMC 7220310. PMID 32426505.
  12. ↑ Sherden NH, et al. (2018). "Identification of iridoid synthases from Nepeta species: Iridoid cyclization does not determine nepetalactone stereochemistry". Phytochemistry. 145: 48–56. Bibcode:2018PChem.145...48S. doi:10.1016/j.phytochem.2017.10.004. PMC 5739345. PMID 29091815.
  13. 1 2 Hill JO, et al. (1976). "Species-characteristic responses to catnip by undomesticated felids". Journal of Chemical Ecology. 2 (2): 239–253. doi:10.1007/BF00987747. S2CID 24240498.
  14. ↑ Resende LS, et al. (2011). "Influence of cinnamon and catnip on the stereotypical pacing of oncilla cats (Leopardus tigrinus) in captivity". Journal of Applied Animal Welfare Science. 14 (3): 247–254. doi:10.1080/10888705.2011.576981. PMID 22044295. S2CID 769991.
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