Hypotensive activity of terpenes found in essential oils

The cardiovascular activity of essential oils has been reported. Some studies showed that the main chemical components of these oils contribute to their pharmacological activity. Therefore, the cardiovascular activity of four monoterpenes and one sesquiterpene was evaluated in the present work. In non-anaesthetized normotensive rats, (+)-alpha-pinene, (-)-beta-pinene, (+/-)-citronellol and (+/-)-linalool (1, 5, 10, and 20 mg/kg, i.v.) induced hypotension [maximal effect: (-35 +/- 3)%, (-46 +/- 4)%, (-48 +/- 2)% and (-40 +/- 2)%, respectively; n=6] and tachycardia [maximal effect: (13 +/- 4)%, (16 +/- 7)%, (21 +/- 1)% and (19 +/- 3)%, respectively; n=6] while (-)-a-bisabolol (1, 5, 10, and 20 mg/kg, i.v.) induced hypotension [maximal effect: (-47 +/- 8)%, n=6] and bradycardia [maximal effect: (-57 +/- 3)%]. In conclusion, these results demonstrated that all terpenes tested had hypotensive activity in rats and that the pharmacological effect of the terpene alcohols was more effective than that of the terpene hydrocarbons.     

Secondary metabolites from Ganoderma lucidum and Spongiporus leucomallellus

The hydrodistillates and solvent extracts of the fruit bodies of Ganoderma lucidum (Fr.) P. Karst. and Spongiporus leucomallellus (Murril) A. David were investigated. The constituents in both oils comprised hydrocarbons, monoterpenes, sesquiterpenes, and fatty acids. Major volatiles of G. lucidum were trans-anethol, R-(-)-linalool, S-(+)-carvone and alpha-bisabolol, while the essential oil of S. leucomallellus contained relatively large amounts of R-(-)-1-octene-3-ol, R-(-)-linalool, 1-hepten-3-one and (Z)-nerolidol. From the n-hexane extract of G. lucidum, the steroid ester ergosta-7,22-diene-3beta-yl pentadecanoate could be identified. From S. leucomallellus two constituents showing structures of 3,4-seco-lanostane type triterpene acids were identified as (+)-23-oxo-3,4-seco-lanosta-4(28),7(8),9(11),24(31)-tetraene-3,26-dicarboxylic acid and (+)-20-hydroxy-23-oxo-3,4-seco-lanosta-4(28),7(8),9(11),24(31)-tetraene3,26-dicarboxylic acid, respectively. Cytotoxicity and antimicrobial activity of selected compounds were investigated using standard tests.     

Assessment of the repellent effect of Lippia alba essential oil and major monoterpenes on the cattle tick Rhipicephalus microplus

The control of Rhipicephalus microplus (Ixodida: Ixodidae) is achieved using synthetic acaricides. However, resistant tick populations are widespread around the world. Plant essential oils can act as repellents, keeping ticks away from hosts and decreasing the selection pressure on synthetic acaricides. The aim of this study was to evaluate the in vitro repellent effect of Lippia alba essential oil on R. microplus larvae. Leaves from two L. alba genotypes maintained under the same agronomic and environmental conditions were collected. Essential oil was extracted by hydrodistillation and analysed by gas chromatography–mass spectrometry (GC‐MS). The major monoterpenes detected in the chemical analysis were commercially acquired and tested. For the repellency test, a glass rod was vertically fixed to measure active climbing of approximately 30 R. microplus larvae aged 14–21 days in response to essential oils and monoterpenes. Repellency was evaluated at 1 h, 3 h and 5 h after treatment. Variation in repellent action was detected between the genotypes. The major monoterpenes identified in the essential oils (limonene and carvone) showed low repellent effects in comparison with intact essential oils. Thus, the present results showed that L. alba essential oil contains bioactive compounds with great repellent activity against ticks that varies according to the plant genotype.     

Radical scavenging activities of Heracleum aquilegifolium Wight (Apiaceae) fruit oils in vitro

The fruits of Heracleum aquilegifolium Wight (Apiaceae) were collected from Western Ghats of the Indian Peninsula. The essential oils were extracted by hydrodistillation. The chemical composition of the essential oils was analysed by gas chromatography and gas chromatography-mass spectrometry (GC-MS). Beta-Pinene (22.3%), 1,8-cineole (20.3%), and beta-phellandrene (12.4%) were the main components of H. aquilegifolium fruit oils. The antioxidant properties of essential oils of H. aquilegifolium were examined by different procedures namely reducing power ability, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, nitric oxide radical scavenging activity, hydrogen peroxide scavenging activity, hydroxyl radical scavenging activity, superoxide anion scavenging activity, and metal chelating activity. The antioxidant activities were compared with those of synthetic antioxidants and standard drugs such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, alpha-tocopherol, curcumin, and quercetin. The study confirmed the possible antioxidant potential of essential oils tested with various in vitro antioxidant methods. The presence of monoterpenes in combination with other components in the oils could be responsible for the activity.     

The pharmacological profile of delta opioid receptor ligands, (+) and (-) TAN-67 on pain modulation

We designed the nonpeptidic highly selective delta opioid receptor agonist on the basis of message address concept and the accessory site theory and synthesized (+/-) TAN-67. In spite of highly potent agonistic activity in in vitro assay, (+/-) TAN-67 (racemate) afforded a weak antinociceptive effect in the mouse tail-flick test. This result led us to separate (+/-) TAN-67 to optical pure compounds, (+) and (-) TAN-67. An i.t.-treatment with (-) TAN-67 produced profound antinociceptive effects through specifically acting on delta1 receptors. Unlike (-) TAN-67, i.t.-administered (+) TAN-67 displayed dose-related nociceptive behaviors such as scratching, biting and licking. The effect of (+) TAN-67 was blocked by i.t.-treatment with NTI (delta receptor antagonist) and (-) TAN-67 (delta1 receptor agonist), but not by morphine (mu receptor agonist). The mechanisms involved in spinal pain modulation induced by (+) and (-) TAN-67 were also described.     

Pharmacological activity of (R)-(+)-pulegone, a chemical constituent of essential oils

(R)-(+)-Pulegone is a monoterpene found in essential oils from plants of the Labiatae family. This compound is a major constituent of Agastache formosanum oil. In this study, the effect of (R)-(+)-pulegone on the central nervous system was evaluated. (R)-(+)-Pulegone caused a significant decrease in ambulation and an increase in pentobarbital-induced sleeping time in mice, indicating a central depressant effect. (+)-Pulegone also significantly increased the latency of convulsions as assessed by the pentylenetetrazole (PTZ) method. The antinociceptive properties of this monoterpene were studied in chemical and thermal models of nociception. Chemical nociception induced in the first and second phase of the subplantar formalin test was significantly inhibited by (R)-(+)-pulegone and was not blocked by naloxone. Thermal nociception was also significantly inhibited while (R)-(+)-pulegone increased the reaction latency of the mice in the hot plate test. These results suggest that (R)-(+)-pulegone is a psychoactive compound and has the profile of an analgesic drug.     

Insecticidal activity of essential oils from eleven Eucalyptus spp. and two hybrids: lethal and sublethal effects of their major components on Blattella germanica

The aim of the current study was to evaluate the fumigant activity of the essential oils from 11 species of the genus Eucalyptus and two of their hybrids on first instar of Blattella germanica L. The fumigant activity and repellence of the four major monoterpene components of these essential oils also were tested. Fumigant activity was evaluated by exposing nymphs to the vapors emitted by 50 microl of essential oil or monoterpene in a closed container. The lowest knockdown time 50% (KT50) values, expressed in minutes, were elicited by the essential oils of the Eucalyptus grandis X Eucalyptus tereticornis (57.9) hybrid, Eucalyptus sideroxylon A. Cunn (62.0), E. grandis X Eucalyptus camaldulensis (63.8) hybrid, Eucalyptus viminalis Labill (64.1), Eucalyptus dunnii Maiden (64.5), and Eucalyptus grandis (Hill) ex Maiden (68.7). The KT50 values for the remaining essential oils ranged between 74.5 (E. saligna Smith) and 161.4 min (E. tereticornis Smith). The essential oil from the hybrid E. grandis X E. tereticornis was 3.7 times less toxic than dichlorvos (positive control). The KT50 values of monoterpenes were 38.8 for alpha-pinene, 55.3 for 1,8-cineole, 175.6 for p-cymene, and 178.3 for gamma-terpinene. Alpha-pinene was 2.5 times less toxic than dichlorvos. There was a strong positive correlation between the fumigant activity of essential oils and their corresponding 1,8-cineole and alpha-pinene concentration. Repellency was quantified using a video tracking system. Two concentrations of monoterpenes were studied (7 and 70 microg/cm2). All compounds produced a light repellent effect but only when applied at 70 microg/cm2. In all cases, the repellent effect was less than that produced by the broad-spectrum insect repellent N,N-diethyl-3-methylbenzamide (positive control).     

Biotransformation of terpenoids by mammals, microorganisms, and plant-cultured cells

This review article summarizes our knowledge of the metabolism of mono- and sesquiterpenoids in mammals, microorganisms, cloned-insect enzymes, and plant-cultured cells. A number of unusual enzymatic reactions and products are reported such as the stereoselective formation of primary alcohols from sterically congested Me2C groups. Such enzymatic processes, including unknown chemical transformations under abiotic conditions, could lead to the discovery of new chemical reactions and might be helpful in the design of new drugs. The transformations of the following mono- and sesquiterpenoids (in alphabetical order) are discussed: (+)-(1R)-aromadendrene (61), (-)-allo-aromadendrene (62), (+/-)-camphene (21), (-)-cis-carane (20), (+)-3-carene (17), (+/-)-carvone (27), (-)-beta-caryophyllene (43), (+)-cedrol (35), cuminaldehyde (25), (+)-curdione (69), (-)-cyclocolorenone (60), (-)-elemol (51), (2E,6E)-farnesol (31), germacrone (67), ginsenol (40), (-)-globulol (63), isoprobotryan-9alpha-ol (82a), juvenile hormone III (33), (+)-ledol (65), (+)-longifolene (46), myrcene (3), (-)-myrtenal (23), (+)-nootkatone (48), patchouli alcohol (37), (-)-perillaldehyde (24), (-)-alpha- and beta-pinene (8 and 9), alpha-santalol (28), (-)-6beta-santonin (83a), 6beta-tetrahydrosantonin (83b), beta-selinene (57), alpha-thujone (26a), beta-thujone (26b), T-2 toxin (87), and valerianol (53).     

Chemical variation of essential oil constituents of Ocimum gratissimum L. from Benin, and impact on antimicrobial properties and toxicity against Artemia salina leach

To determine the period of harvest that optimizes the antimicrobial activities of the essential oil of Ocimum gratissimum L. from Benin, aerial plant parts were collected at two vegetative stages (pre- and full-flowering) and three sampling times (7?am, 1?pm, and 7?pm). Extraction by hydrodistillation yielded between 0.65 and 0.78% of essential oils. Characterization of the oils by GC-FID and GC/MS analysis revealed the presence of monoterpenes (87.26-93.81%), sesquiterpenes (5.57-11.34%), and aliphatic compounds (0.15-0.18%), with p-cymene (1; 28.08-53.82%), thymol (2; 3.32-29.13%), γ-terpinene (3; 1.11-10.91%), α-thujene (4; 3.37-10.77%), and β-myrcene (5; 4.24-8.28%) as major components. Two chemotypes were observed, i.e., a p-cymene/thymol and a p-cymene chemotype, for plants harvested at 7?am for the former and at 1?pm or 7?pm for the latter, respectively. The oils were fungicidal against Candida albicans, with the sample from full-flowering plants collected at 7?am being the most active (MIC?=?0.06±0.00?mg/ml). The chemical variation of the oils also influenced the antimicrobial effect against Staphylococcus aureus; the most active oil was obtained from plants at the pre-flowering stage collected at 7?am (MIC=0.24±0.01?mg/ml). Escherichia coli was insensitive to the chemical variation of the oils (MICs of ca. 0.48±0.02?mg/ml for all oils). Moreover, the essential oils showed low toxicity against Artemia salina Leach larvae, with LC(50) values in the range of 43-146?μg/ml. This is the first study of the interaction between the daytime of collection and vegetative stage of the plants and the antimicrobial properties and toxicity of the essential oil of O. gratissimum from Benin.     

Limonene: attractant kairomone for white pine cone beetles (Coleoptera: Scolytidae) in an eastern white pine seed orchard in western North Carolina

I report on the attraction of the white pine cone beetle, Conophthoru.s coniperda (Schwarz) (Coleoptera: Scolytidae), to traps baited with the host monoterpene limonene in western North Carolina. Both (+)- and (-)-limonene attracted male and female cone beetles to Japanese beetle traps in an eastern white pine, Pinus strobus L., seed orchard near Murphy, NC. Catches of cone beetles were directly proportional to the release rate of (-)-limonene; (+)-limonene was not tested for dose response. Attraction of cone beetles to the pheromone (+/-)-trans-pityol was increased significantly by both enantiomers of limonene. In all experiments, catches of C. coniperda were strongly male biased with no treatment effect on sex ratio. (- )-Limonene had no effect on trap catches of the predator Enoclerus nigripes (Say) to pityol, whereas (+)-limonene interrupted the attraction of E. nigripes to traps baited with pityol. Of six monoterpenes commonly found in white pine cones, only (-)-alpha-pinene elicited attraction of E. nigripes to Japanese beetle traps.     

Spontaneous mutagenesis is enhanced in Apex heterozygous mice

Germ line DNA directs the development of the next generation and, as such, is profoundly different from somatic cell DNA. Spermatogenic cells obtained from young adult lacI transgenic mice display a lower spontaneous mutant frequency and greater in vitro base excision repair activity than somatic cells and tissues obtained from the same mice. However, spermatogenic cells from old lacI mice display a 10-fold higher mutant frequency. This increased spontaneous mutant frequency occurs coincidentally with decreased in vitro base excision repair activity for germ cell and testicular extracts that in turn corresponds to a decreased abundance of AP endonuclease. To directly test whether a genetic diminution of AP endonuclease results in increased spontaneous mutant frequencies in spermatogenic cell types, AP endonuclease heterozygous (Apex(+/-)) knockout mice were crossed with lacI transgenic mice. Spontaneous mutant frequencies were significantly elevated (approximately twofold) for liver and spleen obtained from 3-month-old Apex(+/-) lacI(+) mice compared to frequencies from Apex(+/+) lacI(+) littermates and were additionally elevated for somatic tissues from 9-month-old mice. Spermatogenic cells from 9-month-old Apex(+/-) lacI(+) mice were significantly elevated twofold compared to levels for 9-month-old Apex(+/+) lacI(+) control mice. These data indicate that diminution of AP endonuclease has a significant effect on spontaneous mutagenesis in somatic and germ line cells.     

Inhaled linalool-induced sedation in mice

Linalool is a monoterpene often found as a major component of essential oils obtained from aromatic plant species, many of which are used in traditional medical systems as hypno-sedatives. Psychopharmacological evaluations of linalool (i.p. and i.c.v.) revealed marked sedative and anticonvulsant central effects in various mouse models. Considering this profile and alleged effects of inhaled lavender essential oil, the purpose of this study was to examine the sedative effects of inhaled linalool in mice. Mice were placed in an inhalation chamber during 60 min, in an atmosphere saturated with 1% or 3% linalool.Immediately after inhalation, animals were evaluated regarding locomotion, barbiturate-induced sleeping time, body temperature and motor coordination (rota-rod test). The 1% and 3% linalool increased (p<0.01) pentobarbital sleeping time and reduced (p<0.01) body temperature. The 3% linalool decreased (p<0.01) locomotion. Motor coordination was not affected. Hence, linalool inhaled for 1 h seems to induce sedation without significant impairment in motor abilities, a side effect shared by most psycholeptic drugs.     

Effect of monoterpenes on growth of cellular slime mold,Dictyostelium discoideum Ax-2

We examined 12 important monoterpenes found on the forest floor underPinus thunbergii, and monitored their effect on the growth of a slime mold,Dictyostelium discoideum Ax-2. Four concentrations were tested for each compound (3.3, 0.33, 0.033, and 0.0033 μ/mL). Relative growth rates were determined by comparing the cell counts of treated organisms with those from the controls. At a concentration of 3.3 μlml, (1S)-(-)-α-pinene, (-)-menthone, (-)-camphene, (S)-(+)-carvone, and (1 R)-(-)-fenchone strongly inhibited the development of this slime mold. In contrast, (+)-sabinene, (R)-(+)-limonene, and myrcene showed no inhibitory effects, even at the highest concentration tested. By comparing individual growth rates with the control during the incubation period, we could classify these monoterpenes into three groups: I., compounds that were able to inhibit Ax-2 growth at all concentrations; II., compounds that showed a strong inhibitory effect at treatments between 3.3 and 0.033 μl/mL, and mild anti-microbial activity at the lowest concentration; and III., compounds that inhibited growth at higher concentrations (3.3 and 0.33 μl/mL), but enhanced it at lower levels (0.033 and 0.0033 μ/ml.). Based on these results, we suggest that the inhibitory and enhancing effects of selected monoterpenes depend upon the concentration of the individual compound.     

A new sigma ligand, (+/-)-PPCC, antagonizes kappa opioid receptor-mediated antinociceptive effect

The compound (1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(+/-)-PPCC] is a ligand with high affinity for sigma (sigma) sites of which the selectivity towards several other receptor systems has been demonstrated. Given the existence of a relationship between the sigma system and the kappa opioid (KOP)-mediated analgesia, to characterize the pharmacological properties of (+/-)-PPCC we analyzed its influence on the analgesic effect of the systemic injected kappa agonist (-)-U-50,488H comparing the effects with those shown by (+)-pentazocine and BD1047. The results demonstrate that the systemic administration of (+/-)-PPCC (1 mg/kg s.c.) does not modify basal tail-flick latency. Pre-treatment with (+/-)-PPCC, at the same dose, significantly decreased the antinociceptive effect of (-)-U-50,488H, analogously to the sigma compounds used. This study confirms that (+/-)-PPCC plays the role of sigma agonist in this model and strengthens the hypothesis of the sigma receptor modulatory role on KOP-mediated analgesia.     

Chemical polymorphism of the essential oils from populations of Thymus caespititius grown on the island S. Jorge (Azores)

The compositions of the essential oils obtained from ten populations of Thymus caespititius grown on S. Jorge (Azores) were studied by GC and GC-MS. All the oils analysed were dominated by their monoterpene fraction (69-9%). The sesquiterpene fraction was rather small (4-17%) and consisted mainly of oxygen-containing compounds (3-13%). Enantiomeric ratio of sabinene and alpha-terpineol was investigated in the oils from some populations. (+)-Sabinene was detected with high enatiomeric purity (96 99%). Although ( +)-alpha terpineol was the predominant enantiomer, its purity varied considerably (66-97%). Cluster analysis of all identified components grouped the oils into four main clusters that corresponded with their major components: alpha-terpineol (43-68%), carvacrol (32-52%), thymol (44-58%) and sabinene (41%). The essential oil from Th. caespititius showed a clear chemical polymorphism, that was particularly evident among four populations growing along a 200 m distance at Pico Verde.     

Chemodiversity of Essential Oils from Nine Species of Celastraceae

Extracts and compounds obtained from several species of Celastraceae family are reported as potential sources of drugs due to their diverse pharmacological properties. Nevertheless, essential oil composition from these species is still little known. This work aimed at the analysis of essential oils obtained from different Brazilian Celastraceae species. A total of seventeen oils were obtained using hydrodistillation process and analyzed by gas chromatography/mass spectrometry (GC/MS). Principal component analysis (PCA) allowed the identification of a chemical composition pattern among the analyzed essential oils. Some compounds were more frequent among Celastraceae species, such as cis‐ and trans‐linalool oxide (14/17 oil samples), nerylacetone (13/17), linalool (11/17), β‐ionone (10/17), α‐ionone (9/17), nerolidol (10/17), decanal (10/17), and dodecanoic acid (10/17). These results contribute to the chemophenetics of Celastraceae species.     

Essential oils from two endemic species of Apiaceae from Iran

The composition of essential oils of Leutea glaucopruinosa (Rech.f.) Akhani & Salimian comb. nov., and Zeravschania (Boiss. & Hausskn.) Salimian & Akhani comb. nov. were analysed by GC-MS. 49 compounds are identified in the former and 33 compounds in the latter, comprising a total of 76 compounds in both species. Both species were originally described under Peucedanum, which are transferred in this paper into Leutea and Zeravschania, respectively. The chemical compounds of the essential oils show that there are only seven common compounds between two species. The major compounds of L. glaucopruinosa are mostly monoterpene hydrocarbons and oxygenated monoterpenes, in which alpha-pinene (31.5%), sabinene (9.7%), beta-pinene (9.2%), exo-fenchyl acetate (4.5%) are dominant. In Z. pastinacifolia sesquiterpene hydrocarbons and phenylpropanoids dominate with beta-bisabolene (37.3%), 3,1-butyl-1,2-dimethoxy benzene (14.9%), 10,11-dimethylbicyclo[6.3.0]undec-(8)-en-9-one (12.9%), 4-t-butyl-1,2-dimethoxy benzene (6.8%), (E)-asarone (5.1%) and elemicine (4.1%) as major compounds.     

Essential oils from micropropagated plants of Lavandula viridis

The essential oils of Lavandula viridis were analysed by GC and GC-MS. Comparisons were made between three types of plant material from the same clone: field-grown plant, in vitro shoot cultures and micropropagated plants of the same clone. The most common components usually found in lavender oils were present in the oil samples analysed and more than 45 constituents were identified, representing more than 80% of the essential oil. The essential oils analysed consisted mainly of monoterpenes (75.4-76.3%), where oxygenated and hydrocarbons identified ranged from 41.8 to 57.3% and 18.1 to 34.2%, respectively. The major components found were 1.8-cineole (18.2-25.1%), camphor (9.1-15.7%), alpha-pinene (8.8-14.1%), borneol (4.1-4.8%), beta-pinene (1.2-5.6%), delta 3-carene (1.0-6.5%) and alpha-terpineol (0.8-4.2%). The monoterpene fraction of the in vitro shoot cultures showed different relative amounts of hydrocarbons and oxygenated components in relation to the parent plant and to micropropagated plants. In the sesquiterpene hydrocarbon fraction of the oil samples analysed (6.1-8.2%), 7-epi-alpha-selinene (1.6-4.8%) was the most important component and the oxygenated sesquiterpenes were found in small amounts (1.1-1.7%). The essential oils from field-grown plants of L. viridis, when compared with those obtained from in vitro shoot cultures or micropropagated plants of the same clone, demonstrated that the same major components were found without significant compositional variations.     

Molecular modeling, structure--activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors.

We previously disclosed the discovery of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3) as a novel class of dopamine transporter (DAT) inhibitors and showed that (+/-)-3 has a significant functional antagonism against cocaine in vitro. Our previous preliminary structure-activity relationship study led to identification of a more potent DAT inhibitor [(+/-)-4] but this compound failed to show any significant functional antagonism. To search for more potent analogues than 3 but still displaying significant functional antagonism, further SARs, molecular modeling studies and in vitro pharmacological evaluation of this novel class of DAT inhibitors were performed. Sixteen new analogues were synthesized in racemic form and evaluated as DAT inhibitors. It was found that seven new analogues are reasonably potent DAT inhibitors with K(i) values of 0.041--0.30 and 0.052--0.16 microM in [(3)H]mazindol binding and inhibition of DA reuptake. Chiral isomers of several potent DAT inhibitors were obtained through chiral HPLC separation and evaluated as inhibitors at all the three monoamine transporter sites. In general, the (-)-isomer is more active than the (+)-isomer in inhibition of DA reuptake and all the (-)-isomers are selective inhibitors at the DAT site. Evaluation of cocaine's effect on dopamine uptake in the presence and absence of (+)-3 and (-)-3 showed that (-)-3 is responsible for the functional antagonism obtained with the original lead (+/-)-3. Out of the new compounds synthesized, analogue (+/-)-20, which is 8- and 3-fold more potent than (+/-)-3 in binding and inhibition of DA reuptake, appeared to have improved functional antagonism as compared to (+/-)-3.