Linalool 1 is an odorant that is commonly perceived as having a pleasant odor, but is also known to elicit physiological effects such as inducing calmness and enhancing sleep. However, no comprehensive studies are at hand to show which structural features are responsible for these prominent effects. Therefore, a total of six oxygenated derivatives were synthesized from both 1 and linalyl acetate 2, and were tested for their odor qualities and relative odor thresholds (OTs) in air. Linalool was found to be the most potent odorant among the investigated compounds, with an average OT of 3.2 ng/L, while the 8-hydroxylinalool derivative was the least odorous compound with an OT of 160 ng/L; 8-carboxylinalool was found to be odorless. The odorant 8-oxolinalyl acetate, which has very similar odor properties to linalool, was the most potent odorant besides linalool, exhibiting an OT of 5.9 ng/L. By comparison, 8-carboxylinalyl acetate had a similar OT (6.1 ng/L) as its corresponding 8-oxo derivative but exhibited divergent odor properties (fatty, greasy, musty). Overall, oxygenation on carbon 8 had a substantial effect on the aroma profiles of structural derivatives of linalool and linalyl acetate.
Despite being isomers having the same citrus-like, floral odor, geraniol, 1, and nerol, 3, show different odor thresholds. To date, no systematic studies are at hand elucidating the structural features required for their specific odor properties. Therefore, starting from these two basic structures and their corresponding esters, namely, geranyl acetate, 2, and neryl acetate, 4, a total of 12 oxygenated compounds were synthesized and characterized regarding retention indices (RI), mass spectrometric (MS), and nuclear magnetic resonance (NMR) data. All compounds were individually tested for their odor qualities and odor thresholds in air (OT). Geraniol, the Z-isomer, with an OT of 14 ng/L, was found to be more potent than its E-isomer, nerol, which has an OT of 60 ng/L. However, 8-oxoneryl acetate was the most potent derivative within this study, exhibiting an OT of 8.8 ng/L, whereas 8-oxonerol was the least potent with an OT of 493 ng/L. Interestingly, the 8-oxo derivatives smell musty and fatty, whereas the 8-hydroxy derivatives show odor impressions similar to those of 1 and 3. 8-Carboxygeraniol was found to be odorless, whereas its E-isomer, 8-carboxynerol, showed fatty, waxy, and greasy impressions. Overall, we observed that oxygenation on C-8 affects mainly the odor quality, whereas the E/ Z position of the functional group on C-1 affects the odor potency.
Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory α1β2 GABAA receptors in various expression systems. However, in plants or humans, i.e., following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives. Here, we analyzed the modulatory potential of linalool derivatives at α1β2γ2 GABAA receptors upon transient overexpression. Following receptor expression control, electrophysiological recordings in a whole cell configuration were used to determine the chloride influx upon co-application of GABA EC10−30 together with the modulatory substance. Our results show that only oxygenated linalool metabolites at carbon 8 positively affect GABAergic currents whereas derivatives hydroxylated or carboxylated at carbon 8 were rather ineffective. Acetylated linalool derivatives resulted in non-significant changes of GABAergic currents. We can conclude that metabolism of linalool reduces its positive allosteric potential at GABAA receptors compared to the significant potentiation effects of the parent molecule linalool itself.
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