A review of environmental odor quantification and qualification methods: The question of objectivity in sensory analysis.

For several years, various issues have up surged linked to odor nuisances with impacts on health and economic concerns. As awareness grew, recent development in instrumental techniques and sensorial analysis have emerged offering efficient and complementary approaches regarding environmental odor monitoring and control. While chemical analysis faces several obstacles, the sensory approach can help overcome them. Therefore, this latter may be considered as subjective, putting the reliability of the studies at risk. This paper is a review of the most commonly sensory methodology used for quantitative and qualitative environmental assessment of odor intensity (OI), odor concentration (OC), odor nature (ON) and hedonic tone (HT). For each of these odor dimensions, the assessment techniques are presented and compared: panel characteristics are discussed; laboratory and field studies are considered and the objectivity of the results is debated. For odor quantification, the use of a reference scale for OI assessment offers less subjectivity than other techniques but at the expense of ease-of-use. For OC assessment, the use of dynamic olfactometry was shown to be the least biased. For odor qualification, the ON description was less subjective when a reference-based lexicon was used but at the expense of simplicity, cost, and lesser panel-training requirements. Only when assessing HT was subjectivity an accepted feature because it reflects the impacted communities' acceptance of odorous emissions. For all discussed dimensions, field studies were shown to be the least biased due to the absence of air sampling, except for OC, where the dispersion modeling approach also showed great potential. In conclusion, this paper offers the reader a guide for environmental odor sensory analysis with the capacity to choose among different methods depending on the study nature, expectations, and capacities.

Objective odor analysis of incidentally emitted compounds using the Langage des Nez® method: application to the industrial zone of Le Havre.

Environmental odor studies are usually done using two approaches: nuisance impact assessment and source identification. The latter may be done using chemical analysis or sensory analysis. While sensory analyses offer many advantages, they also face the main obstacle: odor nature description still uses conventional methods based on subjective evocations as odor descriptors. This makes the sensory method ineffective especially when the expected outcome is the source identification in the context of an industrial accident. This work wants to fulfill this gap proposing to build an objective database including the odor nature description of selected potentially emitted compounds using a promising approach: the Langage des Nez® (LdN). Using definite odorous compounds as odor referents, this work provides the odor nature description of 44 compounds, reported as potential incidentally released chemical compounds in the industrial zone of Le Havre. The city of Le Havre, France, was chosen as a model due to a history of odorous emissions of industrial origins. A trained panel described the odor of each compound using up to three referents of the LdN referents collection and attributed a score to each referent. A data analysis method was developed based on the frequency of citation of the referents and the attributed scores allowing the categorization of each compound in three types of consensus categories. The data analysis results showed that around 80% of compounds were described with a good consensus, showing the LdN as a well-adapted lexicon. This study does not point to any correlation between the chemical structures of the compounds of interest and their relative referents. When compared to conventional methods, LdN revealed a more objective and precise approach. The proposed experimental method and the results provided in this work offer the first insight for time-efficient approaches to objectively describe environmental odors, especially potentially emitted odors during incidents. This work may be supplemented by abatement and mixture effect investigations for a complete understanding of odor dispersion.

Discovery of SAR184841, a potent and long-lasting inhibitor of 11ß-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D.

Starting from 11ß-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11ß-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

Pyrrolidine-pyrazole ureas as potent and selective inhibitors of 11ß-hydroxysteroid-dehydrogenase type 1.

A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11ß-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11ß-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues.

Mutant 5-hydroxytryptamine 1A receptor D116A is a receptor activated solely by synthetic ligands with a rich pharmacology.

Like other biogenic amine G protein-coupled receptors, mutation of the conserved aspartatic residue into alanine at position 116 (D116A(3.32)) in the 5-hydroxytryptamine (5-HT)(1A) receptor greatly affects 5-HT binding and signal transduction. [(3)H]8-Hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and [(3)H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100,635) are capable to bind the 5-HT(1A)-D116A mutant and, using these radioligands, we show here that this mutation dramatically reduces the affinities of the selective 5-HT(1A) agonists N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-methylamino methyl]piperidine (F13640), 3-chloro-4-fluorophenyl-(4-fluorophenyl-4-{[(5-methyl-6 methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone (F13714), and 2-[5-[3-(4-methylsulfonylamino)benzyl-1,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694247) and that of 5-carboxamidotryptamine. Although to a lesser extent, the binding of buspirone, (+)-flesinoxan, (-)-pindolol, and (-)-8-OH-DPAT are also highly decreased. In contrast, affinities of the 5-HT(1A) ligands WAY100,635, spiperone, (-)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz {c,d}indole-6-carboxamide (LY228,729), and 1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl) piperazine (S14506) and the prototypical 5-HT(1A) agonist (+)-8-OH-DPAT are only slightly affected by the mutation, suggesting a moderate contribution of Asp116 to the binding pocket for these latter. Furthermore, LY228,729, S14506, and (+)-8-OH-DPAT induce a potent and efficacious coupling of the 5-HT(1A)-D116A receptor to G protein activation as measured by Ca(2+) mobilization and guanosine 5'-O-(3-[(35)S]thio)triphosphate binding in Chinese hamster ovary cells as well as by G protein-coupled inwardly rectifying potassium channel current activation in Xenopus laevis oocytes. It is interesting that the selective 5-HT(1A) antagonist WAY100,635 shows potent partial agonist activity at the 5-HT(1A)-D116A mutant, whereas spiperone maintains its inverse agonist properties. The pharmacological approach reported here re-evaluates the binding and functional properties of the 5-HT(1A)-D116A receptor and describes for the first time this mutant as a receptor activated solely by synthetic ligands (RASSL), with a rich pharmacology. By bioengineering animal models incorporating this RASSL, one may further explore the role of 5-HT(1A) receptor signaling in the central nervous system as well as G(i) protein-mediated signaling pathways in other tissues.