*2.6. Inuviscolide*

The guaianoline-type sesquiterpene lactone inuviscolide (**6**) (C15 H20 O3) (Figure 7) was identified in *Ferula communis* (Apiaceae) and described to be the main metabolite in *Inula viscosa* (L.) Ait. [154].

Inuviscolide (**6**) inhibited in vivo inflammation in mice, as shown in the investigation performed by Hernández et al. [155]. The authors used inuviscolide (**6**) and ilicic acid from *Inula viscosa* and found that compound **6** influenced cell degranulation and leukotriene biosynthesis, as well as neurogenic drive and glucocorticoid-like interactions. During the testing, ear and paw edema were induced in Swiss female mice using phorbol esters or ethyl phenylpropiolate (EPP), and phospholipase A2 (PLA2) or serotonin, respectively. The drug dose was applied topically in the ear models but as subcutaneous or intraperitoneal injections in the paw models. For quantitation of leukotriene B4 (LTB4) formation, high-performance liquid chromatography (HPLC) was performed on rat peritoneal neutrophils. The results showed that compound **6** reduced PLA2-induced edema with an ID50 of 98 μmol/kg. The results did not indicate that glucocorticoid response modifiers had an influence on the edema induced by serotonin. In intact cells, inuviscolide (**6**) resulted in reduced generation of LTB4 (IC50 value of 94 μM). The overall results indicated that compound **6** has an important role in the anti-inflammatory activity of *Inula viscosa*, being more active than ilicic acid. The action mechanism was suggested to be related to an interference with leukotriene synthesis and to PLA2-induced mastocyte release of inflammatory mediators [156].

**Figure 7.** Structure of inuviscolide (**6**).

#### *2.7. Lactucin and Its Derivatives Lactupicrin, and Lactucopicrin*

Other compounds from the guaianolide subclass are lactucin (**7**) (C15H16O5) and its 8- and 15- (4-hydroxyphenylacetate) derivatives lactupicrin (**8**) and lactucopicrin (**9**), respectively (Figure 8). Dolejš et al. [156] and Ruban et al. [157] had previously described the chemical structure of lactucin (**7**). These compounds are distributed within Asteraceae like *Lactuca serriola* [158], especially plants commonly used in salads. *Lactuca sativa* (lettuce), *Cichorium intybus* (chicory and radicchio), and *Cichorium endivia* (endive) have been reported to contain lactucin (**7**) and lactucin-related substances [159–164]. The content depends largely on the species, variety and the part of the plant analyzed. In fact, lettuce guaianolide content was high and reached concentrations between 61.7 mg/mL and 147.1 mg/mL in its latex [160] and 2.9 mg/g to 36.1 mg/g in the overall plant, expressed as dry weight [162].

**Figure 8.** Structures of lactucin (**7**) and its derivatives lactupicrin (**8**) and lactucopicrin (**9**).

The biological activities of lactucin (**7**) and lactucin-related compounds had already attracted interest at the end of the 19th century, as they were credited to be responsible for the bitter taste and pharmacological effect of lactucarium or lettuce opium [165]. This is the condensed latex of wild lettuce *Lactuca virosa*. This dried exudate was used in Europe for centuries with similar applications to opium as an analgesic, antitussive, and sedative [163]. Due to its widespread use, it was described and standardized in the United States Pharmacopoeia (USP) and the British Pharmaceutical Codex as a sedative for irritable cough and as a mild hypnotic for insomnia [166–168]. Lactucopicrin (**9**) and lactucin (**7**) were identified as its major active compounds, although compound **7** was suggested to be one of the main metabolites related to the sedative and the sleep-promoting effects [163]. In an in vivo study in mice, both substances were confirmed to be analgesics, with an activity equal to or greater than ibuprofen. In addition, when lactucin (**7**) and lactucopicrin (**9**) were administered to mice on the hot plate, both compounds were revealed to have analgesic and sedative e ffects at concentrations of 15 and 30 mg/kg, respectively. Furthermore, in a spontaneous locomotor activity test, these compounds were active at concentrations of 30 mg/kg [168].

Although the pure compounds currently are not easily available on the market, several lettuce extracts and seed oils containing these sesquiterpene lactones as main active compounds are commercialized, e.g., Sedan ® (Pharco Pharmaceutical Company, Egypt). The sedative e ffects were addressed in the pilot study by Yakoot et al. [169]. The authors investigated if lettuce seed oil was efficient and safe to treat patients with sleep disorders. The results showed that the seed oil of *L. sativa* was a potentially hazard-free agent, able to reduce sleeping di fficulties and alleviate mild to moderate forms of anxiety in geriatric patients, without showing side e ffects [169,170]. Additionally, the study performed by Kim et al. [163] examined the sleep-inducing and sleep-prolonging e ffect of four lettuce varieties. The seed and leaf extracts were evaluated using a four-week-old ICR mouse model to analyze their e ffects on pentobarbital-induced sleep. The results showed that both extract types lengthened sleep duration and significantly reduced sleep latency at both evaluated doses of 80 mg/kg and of 160 mg/kg [163]. Although these studies in patients were performed with plant extracts reported to contain lactucin (**7**) and its derivatives as principal active pharmacological compounds, they confirm that their application for treatment of anxiety and sleep disorders is worthy of further evaluation. Additionally, the results showed that these sesquiterpenes might be assessed as potential alternatives to currently used sleep-promoting, sedative, and anxiolytic agents, with their varied negative side-e ffects and addiction-potential.
