'Sniffin' Sticks': Olfactory Performance Assessed by the Combined Testing of Odour Identification, Odor Discrimination and Olfactory Threshold

‘Sniffin’ Sticks' is a new test of nasal chemosensoryperformance based on pen-like odor dispensing devices. It comprisesthree tests of olfactory function, namely tests for odor threshold(n-butanol, testing by means of a single staircase), odor discrimination(15 pairs of odorants, triple forced choice) and odor identification(16 common odorants, multiple forced choice from four verbalitems per test odorant). After extensive preliminary investigationsthe tests were applied to a group of 104 healthy volunteers(52 female, 52 male, mean age 49.5 years, range 18–84years) in order to establish test-retest reliability and tocompare them with an established measure of olfactory performance(the Connecticut Chemosensory Clinical Research Center Test,CCCRC). Performance decreased with increasing age of the subjects(     

Concentration-dependent changes of perceived odor quality

In order to assess the dependence of perceived odor qualityon odorant concentration, we studied 21 subjects. For eightsubjects all possible pairs from a pool of six odorants at threedecimal dilutions were presented, and subjects were requestedto state whether members of the pair were qualitatively ‘similar’or ‘different’ It was found that while pairs withthe same odorant at identical concentrations were judged ‘similar’in >90% of the cases by all subjects, scores went down to10% ‘similar’ judgements in some cases when thesame odorant was presented at a 100-fold concentration difference.Large time-invariable differences were found among subjectsand among odorants. For the additional 13 subjects, all possiblepairs from a pool of four odorants at three decimal dilutionswere presented. Subjects were instructed to state whether membersof the pair were qualitatively ‘same’ or ‘different’,and were also requested to rank the degree of difference ona visual analogue scale. Results for this group were, in general,similar to the results of the former group of subjects and goodagreement between the two tasks was found. The results suggestthat variations in olfactory stimulus magnitude may be perceivedas quality differences, as previously shown for vision and audition.     

Cognitive Processes in Odorant Mixture Assessment

‘Comparison of models of odor interaction’ by Cainand his colleagues (1995) is a turning point in assessment ofthe strengths of smell of mixtures of odorants. Their paperprovides the best empirical comparison to date of models of(olfactory) binary mixture intensities and combines this analysiswith a cogent critique of the whole tradition of mixture psychophysics.This commentary on their paper argues that their critique isnot radical enough. Chem. Senses 20: 639–643, 1995.     

Reversal of hyposmia in laryngectomized patients

To assess the degree to which the olfactory deficit associatedwith laryngectomy is simply due to the loss of nasal airflow,17 laryngectomees were fitted with a device (larynx bypass)which allowed them to produce approximately normal sniffs. Detectionthresholds were determined for two odorants, vanillin (reportedlyexcites only the olfactory nerve) and ammonia (a strong trigeminalirritant). Without the bypass nine patients detected neitherodorant. The others, who could manoeuver somewhat more vigorousnasal airflows, detected the odorants but only half had ‘normal’thresholds. In this latter group there was a tendency for decreasingdetection thresholds with increasing postoperative years. Withthe bypass all 17 patients achieved ‘normal’ ammoniathresholds whereas 10 achieved ‘normal’ vanillinthresholds. Thus, the loss of nasal airflow is a major contributorto the olfactory deficit of laryngectomy, and it may be theonly contributor for trigeminal irritants like ammonia. On theother hand, for non-trigeminal stimuli like vanillin other factorsseem to be involved.     

Synthesis and comparative molecular field analysis (CoMFA) of antitumor 3-arylisoquinoline derivatives

In this study a series of 3-arylisoquinoline derivatives were synthesized and cytotoxicity against human melanoma tumor cell evaluated, and a three dimensional quantitative structure—activity relationship was investigated using the comparative molecular field analysis (CoMFA). The results suggested that the electrostatic, steric and hydrophobic factors of 3-arylisoquinolines were strongly correlated with the antitumor activity. Considerable predictive ability (cross-validated r² as high as 0.721) was obtained through CoMFA.     

CoMFA and CoMSIA 3D-QSAR analysis of DMDP derivatives as anti-cancer agents

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (78 compounds) of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as potent anticancer agents. The best prediction were obtained with a CoMFA standard model (q(2) = 0.530, r(2) = 0.903) and with CoMSIA combined steric, electrostatic, hydrophobic and hydrogen bond donor fields (q(2) = 0.548, r(2) = 0.909). Both models were validated by a test set of ten compounds producing very good predictive r(2) values of 0.935 and 0.842, respectively. CoMFA and CoMSIA contour maps were then used to analyze the structural features of ligands to account for the activity in terms of positively contributing physiochemical properties such as steric, electrostatic, hydrophobic and hydrogen bond donor fields. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. This study suggests that the highly electropositive substituents with low steric tolerance are required at 5 position of the pteridine ring and bulky electronegatve substituents are required at the meta-position of the phenyl ring. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for the design of deazapteridine-based analogs as anticancer agents.     

CoMFA and CoMSIA 3D-QSAR analysis of diaryloxy-methano-phenanthrene derivatives as anti-tubercular agents

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (44 compounds) of diaryloxy-methano-phenanthrene derivatives as potent antitubercular agents. The best predictions were obtained with a CoMFA standard model (q (2)=0.625, r (2)=0.994) and with CoMSIA combined steric, electrostatic, and hydrophobic fields (q (2)=0.486, r (2)=0.986). Both models were validated by a test set of seven compounds and gave satisfactory predictive r (2) values of 0.999 and 0.745, respectively. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands to account for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, and hydrophobic fields. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for further design of phenanthrene-based analogs as anti-TB agents. The resulting contour maps, produced by the best CoMFA and CoMSIA models, were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction-field contour maps also showed a high level of internal consistency. This study suggests that introduction of bulky and highly electronegative groups on the basic amino side chain along with decreasing steric bulk and electronegativity on the phenanthrene ring might be suitable for designing better antitubercular agents.     

MULTIDIMENSIONAL SCALING OF ODORANTS: EXAMINATION OF PSYCHOLOGICAL AND PHYSICOCHEMICAL DIMENSIONS

Nineteen odorants were arranged in a two-dimensional space byALSCAL, a nonmetric multidimensional scaling procedure, on thebasis of similarity of psychological odor quality. Adjectivescales concerning hedonic and ‘tactile’ qualitieswere related to the spatial arrangement Physiocochemical propertiessuch as Raman spectra, Laffort's parameters, and functionalgroup were related to the arrangement as well.     

The 3D-QSAR study of antitumor arylsulfonylimidazolidinone derivatives by CoMFA and CoMSIA

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies for a series of arylsulfonylimidazolidinone derivatives having antitumor activity were conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The in vitro cytotoxicity against human lung carcinoma (A549) exhibited a strong correlation with steric and electrostatic factors of the molecules. Four different types of models have been built using CoMFA and CoMSIA method with AM1 charge or Gasteiger-Huckel charge. By comparison of the statistical results of these models, model I obtained by CoMFA study with AM1 showed the best predictability of the antitumor activities based on the cross-validated value (0.642), conventional r2 (0.981), standard error of estimate (0.106) and PRESS value (0.170).     

Functional activity of the rat olfactory bulb related to different durations of odor exposure

We have studied the effects of different odor exposure durationson the functional activity of the rat olfactory bulb by usingthe 2-deoxyglucose (2-DG) method. This technique brings outodor-specific patterns of labeling in the glomerular layer ofthe bulb. In a first set of experiments, rats designated ascontrols were submitted to two stimulation conditions with cyclohexanonefor 40 min following 2-DG injection: group C-5—alternatestimulation (5 min odor–5 mm pure air); group C-20—continuousstimulation (20 mm odor-20 min pure air). In a second set ofexperiments, rats designated as ‘adapted’ were exposedfor 3 h to cyclohexanone before the 2-DG injection; then, threeconditions of stimulation were tested with the same odor duringthe post-injection period; group Adap-5—alternate stimulation;group Adap-20—continuous stimulation; group Adap-0—stimulationwith pure air only. In the two control groups, the total numbersof labeled glomerular foci were similar; however, group C-20showed a significant increase in the number of ‘heavily’labeled foci. This result suggests that under conditions of20 min continuous odor exposure, receptor cells do not adaptrapidly and totally. Results from the adapted groups showedthat only the group Adap-20 presented significant changes infunctional bulbar activity. An important decrease in the totalnumber of labeled glomerular foci and an absence of ‘heavily’labeled foci were noted in all rats of this group; their patternsof 2-DG uptake were greatly reduced in both complexity and contrast.These results highlight the importance of olfactory receptoradaptation under conditions of long-duration odor exposure.Fast recovery of receptor sensitivity when the stimulation isinterrupted is also suggested.     

Lessons from snail tentacles

The olfactory system of the snail is functionally capable andstructurally complex. The morphology of the olfactory epitheliumand the glomeruli are similar to analogous structures in vertebrates.However, the snail system differs markedly from the vertebratesystem in its lack of a mucus secretion and the apparent absenceof spatial patterning. Such similarities and differences teachus about the limitations and options governing the evolutionof olfactory systems. The comparative approach leads to thefollowing conclusions, or ‘lessons’: (1) Death andreplacement is normal for olfactory receptors. (2) Olfactionrequires large numbers of receptors and other neurons. (3) Glomerularstructures in the olfactory neuropil aid sensory processing.(4) Local interactions are important in the early stages ofolfactory processing. (5) The role of mucus in olfaction ispeculiar to the vertebrate nose. (6) The spatial patterningof odor responses is not necessary for effective odor processing.     

A comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) of N-phenyl-N'-(2-chloroethyl)ureas targeting the colchicine-binding site as anticancer agents

To decipher the mechanism underlying the covalent binding of N-phenyl-N'-(2-chloroethyl)ureas (CEU) to the colchicine-binding site on beta(II)-tubulin and to design new and selective antimitotic drugs, we developed 3D quantitative structure-activity relationships (3D-QSAR) models using CoMFA and CoMSIA analyses. The present study correlates the cell growth inhibition activities of 56 structurally related CEU derivatives to several physicochemical parameters representing steric, electrostatic, and hydrophobic fields. Both CoMFA and CoMSIA models using two different optimum numbers of components (ONC) 10 and 4, respectively, gave good internal predictions and their cross-validated r2 values were between 0.639 and 0.743. These comprehensive CoMFA and CoMSIA models are useful in understanding the structure-activity relationships of CEU. The two models were compared to the X-ray crystal structure of the complex of tubulin-colchicine and analyzed for similarities between the two modes of analysis. These models will inspire the design of new CEU derivatives with enhanced inhibition of tumor cell growth and targeting specificity of beta(II)-tubulin and the cytoskeleton.     

Relationship between the differential adsorption of odorants by the olfactory mucus and their perception in mixtures

It was proposed recently that the differential adsorption ofodorants by the olfactory mucus may constitute the first stepin the processing of odor mixtures [Laing, D.G. (1988) Ann.NY Acad. Sci., 510, 61–66]. In the present study psychophysicalprocedures were used to determine if there was a relationshipbetween differential adsorption by the olfactory mucus and theperception of odorants of different polarity in binary mixtures.With the eight odor pairs studied, differential adsorption andthe polarity of an odorant were not predictors of how well anodorant would be perceived in a mixture or how it would suppressor enhance the perception of other odorants.     

3D-QSAR study of adamantyl N-benzylbenzamides as melanogenesis inhibitors

Three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety were performed to understand the mechanism of action and structure–activity relationship of these compounds. Contour map analysis indicated that steric contributions of the adamantyl moiety and electrostatic contributions of the hydroxyl group at the 3-position are important in the activity. Activities of the training set and test sets predicted by CoMFA fit well with actual activities, demonstrating that CoMFA, along with the best calculated q² value, has the best predictive ability.     

The taste, odor and hedonic quality of polyglycerols

Twenty subjects judged the taste and odor intensity and thetaste and odor pleasantness/unpleasantness of five concentrationsof sucrose, glycerol, a commercial triglycerol, a syntheticlinear diglycerol and a synthetic linear triglycerol. Judgmentsof intensity were made using the method of magnitude estimation;judgments of pleasantness/unpleasantness were made using a graphicline scale. Only the two linear polyglycerols had appreciableodor intensity. Both were described as having an ‘acrid’or ‘burnt caramel’ quality. The odor exponent forthe linear triglycerol was extremely high (1.44) and may beattributed to its intensely unpleasant quality. Sucrose wascharacterized solely by sweet taste, glycerol and the commercialtriglycerol by sweet and bitter tastes, the linear diglycerolby sweet, bitter and sour tastes, and the linear triglycerolby bitter and sour tastes. The relationships between perceivedtaste intensity and concentration were well described by powerfunctions, although the slope of the psychophysical functionfor the linear triglycerol was markedly lower than that forthe other compounds. The relative order of taste intensitieswas: linear triglycerol > sucrose > glycerol = lineardiglycerol > commercial triglycerol. Judgments of taste (andodor) pleasantness/unpleasantness showed only sucrose and glycerolto have positive hedonic qualities. All the polyglycerols werejudged unpleasant at all concentrations. Differences in thetaste and odor characteristics of the commercial and synthetictriglycerols were attributed to the commercial product beinga mixture of over 20 compounds. Although the synthetic lineardi- and triglycerols are effective in lowering water activity,these data suggest that more purified crystalline forms mustbe synthesized before they can be used effectively as humectantsfor intermediate moisture foods.     

Analysis of Odor Discrimination by Multidimensional Scaling at Different Temperatures

Discrimination of odorants by the turtle olfactory bulb at 25°and 37°C was examined by the cross-adaptation techniqueand analysed by multidimensional scaling. Analysis by multidimensionalscaling suggests that at 25°C odorants are grouped accordingto their odor qualities in the turtle olfactory system. At 37°C,the cluster formation of odorants, which have a similar odorquality, such as minty and floral alcohol odorants and molecularstructure, in the plot of multidimensional scaling was poor,indicating that the ability of odor grouping according to theirodor qualities was low at 37°C. Chem. Senses 20: 565–571,1995.     

New studies on odour discrimination in the frog's olfactory receptor cells. I. Experimental results

New experiments were performed within a systematic investigationof the discriminative properties of olfactory receptor cellsin the frog. Extracellular spike responses of receptor unitswere recorded during stimulation with 39 different odorants.Several general properties of the olfactory receptors, alreadydescribed, were confirmed. The overall selectivity was foundto be lower than in previous studies. Enantiomeric forms ofcitronellol and carvone were discriminated by several receptorcells, mainly in quantitative terms. In a series of eight cycloketones,each compound was the best stimulus for at least one receptorcell and some receptor cells had several ‘best stimuli’.Five odorants were delivered at two concentrations. All thereceptors responding to the lowest concentration also respondedto the highest one.     

3D QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies of fullerene-based HIV-1 PR inhibitors

For the first time, a set of experimentally reported [60] fullerene derivatives were subjected to the 3D-QSAR/CoMFA and CoMSIA studies. The aim of this study is to propose a series of novel [60] fullerene-based inhibitors with optimal binding affinity for the HIV-1 PR enzyme. The position of the template molecule at the cavity of HIV-1 PR was optimized and 3D QSAR models were developed. Relative contributions of steric/electrostatic fields of the 3D-QSAR/CoMFA and CoMSIA models have shown that steric effects govern the bioactivity of the compounds, but electrostatic interactions play also an important role.The de novo drug design Leapfrog simulations provided a series of novel compounds with predicted improved inhibition effect.     

SPECIFIC ANOSMIAS TO 5{alpha}-ANDROST-16-EN-3-ONE AND {omega}-PENTADECALACTONE: THE URINOUS AND MUSKY PRIMARY ODORS

About 46% of human subjects are specifically anosmic to theodor of 5-androst-16-en-3- one, and about 9% are specificallyanosmic to the odor of -pentadecalactone. Odor threshold measurementson 33 representative steroids, synthetic musks and related compoundswere made with panels of normal observers and each of thesevarieties of specific anosmics. The androstenone anosmia wasmost pronounced with steroid ketones in the androstane seriesand some isosteric analogs. It is suggested that this specificanosmia corresponds with the absence of a recently-suspectedolfactory primary, the ‘urinous’ odor. The pentadecalactoneanosmia was associated with a number of diverse but approximatelyisosteric synthetic musks. This specific anosmia delineatesmore clearly the boundaries of the ‘musky’ odor,whose probably primacy has long been recognized. Threshold measurementswere made on mixtures of androst-16-en-3-one and pentadecalactone.The results depart little from the ‘rule of additivity’for odor ratios up to 100:1, and suggest a quantitative interpretationfor the anosmic defects measured with single compounds. ^* Permanent address: Istituto di Industrie Agrarie della Universitàdegli Studi, Pisa, Italy.     

Identification of novel 5-hydroxy-1<Emphasis Type="Italic">H</Emphasis>-indole-3-carboxylates with anti-HBV activities based on 3D QSAR studies

Infection with hepatitis B virus (HBV) is a major cause of liver diseases such as cirrhosis and hepatocellular carcinoma. In our previous studies, we identified indole derivatives that have anti-HBV activities. In this study, we optimize a series of 5-hydroxy-1H-indole-3-carboxylates, which exhibited potent anti-HBV activities, using three-dimensional quantitative structure-activity relationship (3D QSAR) studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The lowest energy conformation of compound 3, which exhibited the most potent anti-HBV activity, obtained from systematic search was used as the template for alignment. The best predictions were obtained with the CoMFA standard model (q ² = 0.689, r ² = 0.965, SEE = 0.082, F = 148.751) and with CoMSIA combined steric, electrostatic, hydrophobic and H-bond acceptor fields (q ² = 0.578, r ² = 0.973, SEE = 0.078, F = 100.342). Both models were validated by an external test set of six compounds giving satisfactory prediction. Based on the clues derived from CoMFA and CoMSIA models and their contour maps, another three compounds were designed and synthesized. Pharmacological assay demonstrated that the newly synthesized compounds possessed more potent anti-HBV activities than before (IC₅₀: compound 35a is 3.1 μmol/l, compound 3 is 4.1 μmol/l). Combining the clues derived from the 3D QSAR studies and from further validation of the 3D QSAR models, the activities of the newly synthesized indole derivatives were well accounted for. Furthermore, this showed that the CoMFA and CoMSIA models proved to have good predictive ability.