Patent Application
20240315315
The presently-disclosed subject matter generally relates to methods and devices that use an odorant for suppressing perception of smoke or vapor odor from an inhalation-based nicotine delivery device, such as, for example, cigarette smoke odor. In particular, certain embodiments of the presently-disclosed subject matter relate to methods of smoking or vaping cessation using an odorant or agent for masking an odor. In certain embodiments, an agent for masking the odor of 1-pentanethiol, an agent for masking the odor of guaiacol, or combinations thereof are used. In some embodiments, the method makes use of citronellal, methyl-2-methylbutyrate, or combinations thereof.
Tobacco products, especially cigarettes, are the leading cause of preventable deaths in the U.S. Smoking has a massive negative effect on the health of smokers and on non-smokers exposed passively to cigarette smoke and the chemical residues smoking leaves behind in enclosed spaces. Nicotine from tobacco is readily absorbed into the bloodstream, easily crosses the blood-brain barrier, and activates ionotropic cholinergic receptors in the brain. In the brain's reward circuitry their activation leads to the release of endorphins, a mild euphoric “high”, dopamine release, and consequent reinforcement of smoking behavior.
Although rates of smoking have been declining, about 19% of the U.S. population uses tobacco, and 12% smoke cigarettes. Rates are much higher for socioeconomically disadvantaged people, especially where they are clustered geographically. For example, in the Appalachian regions of Kentucky rates of smoking exceed 30% in some counties, especially in the 18-45 age range. These higher rates are not fully explained by levels of poverty, arguing for contributions by other social factors such as interactions with other smokers. About 8% of adults use e-cigarettes, with tobacco flavors consistently ranking among the top 10 most purchased e-liquids.
Most smokers would like to quit, but historically less than 6% are successful and usually only after repeated attempts. Some pharmacological interventions (e.g., nicotine replacement therapy or varenicline) are showing success, with short-term (3-6 months after treatment) rates of abstinence reaching 25%.
Anecdotes from smoking cessation patients long ago convinced clinicians that cigarette odors trigger the urge to smoke in smokers and reformed smokers, but only recently was this confirmed. Cigarette cravings are increased by cigarette smoke odor, but not by unrelated odors, and pairing artificial cigarette smoke odor with visual cues related to smoking evokes greater neural activity in the brain's reward centers than visual cues alone in smokers.
The olfactory system has intimate connections to reward circuits, something that evolved to reinforce critical behaviors such as learned food preferences. In smokers, the odor of cigarette smoke becomes associated with nicotine's activation of these same reward circuits. In essence, the olfactory reward circuit has been hijacked by nicotine, causing cigarette smoke odor to become a powerful trigger for physiological cravings to smoke.
Accordingly, there remains a need in the art for improved methods of smoking cessation, including effective methods for use by current and former smokers who encounter cigarette smoke odor.
The presently-disclosed subject matter meets some or all of the above-identified needs, as will become evident to those of ordinary skill in the art after a study of information provided in this document.
This Summary describes several embodiments of the presently-disclosed subject matter, and in many cases lists variations and permutations of these embodiments. This Summary is merely exemplary of the numerous and varied embodiments. Mention of one or more representative features of a given embodiment is likewise exemplary. Such an embodiment can typically exist with or without the feature(s) mentioned; likewise, those features can be applied to other embodiments of the presently-disclosed subject matter, whether listed in this Summary or not. To avoid excessive repetition, this Summary does not list or suggest all possible combinations of such features.
The presently-disclosed subject matter includes a method of suppressing perception of smoke or vapor odor from an inhalation-based nicotine delivery device. The presently-disclosed subject matter includes a method of reducing an urge to use an inhalation-based nicotine delivery device. Methods of the presently-disclosed subject matter involve exposing a subject to a composition comprising an agent for masking the odor of 1-pentanethiol, an agent for masking the odor of guaiacol, or combinations thereof.
In some embodiments of the methods disclosed herein, the agent for masking guaiacol is methyl-2-methylbutyrate and the agent for masking 1-pentanethiol is citronellal. In some embodiments of the methods, the composition comprises methyl-2-methylbutyrate and citronellal.
In some embodiments of the methods disclosed herein, exposure to the composition suppresses perception by the subject of the smoke or vapor odor, when the subject is in the presence of the smoke or vapor odor. In some embodiments of the methods, exposure to the composition reduces the urge by the subject to use an inhalation-based nicotine delivery device.
Some embodiments of the methods disclosed herein further involve identifying the subject as a current or past smoker or vapor. Some embodiments of the methods further involve identifying the subject as being at risk of coming into perceptible olfactory proximity to smoke odor or flavoring odor from a tobacco-derived product.
In some embodiments of the methods disclosed herein, the inhalation-based nicotine delivery device is a cigarette, a cigar, a pipe, or a vaping device.
In some embodiments of the methods disclosed herein, exposure involves placing the composition in perceptible olfactory proximity to the subject.
In some embodiments of the methods disclosed herein, the composition is formulated in a liquid, a lotion, a gel, or a topical semi-solid. In some embodiments of the methods, the liquid is a sprayable liquid or a diffusible liquid. In some embodiments of the methods, the composition is provided in a wearable item. In some embodiments of the methods, the wearable item is an adhesive patch, jewelry, clothing, or a device with a refillable cartridge. In some embodiments of the methods, the composition is provided in a diffuser. In some embodiments of the methods, the diffuser is an ultrasonic diffuser, a nebulizing diffuser, an evaporative diffuser, a fan diffuser, a heat diffuser, or a wearable personal diffuser. In some embodiments of the methods, the diffuser is a smart diffuser controlled using a smartphone or smart home system application.
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are used, and the accompanying drawings of which:
The details of one or more embodiments of the presently-disclosed subject matter are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. In case of conflict, the specification of this document, including definitions, will control.
The presently-disclosed subject matter includes methods and devices for suppressing perception of smoke or vapor odor from an inhalation-based nicotine delivery device and/or of reducing an urge to use an inhalation-based nicotine delivery device.
Mammals evolved to cope with a vast universe of millions of structurally diverse volatile chemicals (potential odorants) by expanding the odorant receptor (OR) family into hundreds of genes. OR proteins physically interact with odorants, transducing binding into biochemical events that trigger electrical signals in the olfactory sensory neurons (OSNs). Every OR is capable of responding to a subset of the universe of odorants, and every odorant activates multiple ORs. The complexity of odor detection implied by these facts is resolved by the simplicity of the encoding of olfactory signals. Each OSN expresses only one OR gene. This exquisite specificity allows all of the axons of the OSNs expressing the same OR to converge into the same location in the brain's olfactory bulb, called a glomerulus. Every odor, be it a pure odorant or a mixture, is represented as a distinct spatiotemporal pattern of OSN inputs to glomeruli that depends solely upon which ORs respond. The perception and discrimination of odors are therefore directly dependent on patterns of OR activity and how much these patterns overlap.
When odorants are mixed, behavioral and physiological responses to the mixture are often less than expected from calculating the sum of the responses to the individual odorants. Substantial evidence has accumulated that much of this interaction effect happens at the ORs. The discovery that several of the first few odorants tested for antagonist activity block ORs responsive to other odorants argues that many odorants have this capability. Suppression of ORs is common in vivo when odorants are mixed, and individual odorants are often effective antagonists of multiple unrelated ORs.
Interactions between odorants at ORs can be important for the percept evoked by an odorant mixture because they change the pattern of OR activity. These interactions are one explanation for why most odor mixtures are perceived as unique “odor objects” rather than as the sum of the distinct odorants (“odor elements”) that comprise the mixture. In fact, humans have great difficulty identifying the odorants in mixtures of more than four odorant species. Therefore, even small changes in the OR response pattern have the potential to prevent the perception of cigarette smoke odor, instead evoking a distinctly different percept.
The set of ORs responsive to an odor are directly responsible for the distinct percepts produced by odors, and differences in OR response patterns are fundamental to odor discrimination. Masking odors are effective ways to prevent perception of unwanted odors, often referred to as malodors. A masking odor draws attention away from a malodor or reduces recognition of a malodor. Masking odors are the basis for most air freshener products (excluding Febreze®, which uses β-cyclodextrin to trap odor molecules). Mechanistically, a typical masking odor produces a neural response pattern that overwhelms the malodor's response pattern. Most simply, the malodor's response pattern is strong and broad enough to obscure the malodor response pattern and produce a distinctly different percept.
Most effective would be a blocking odor or chemical that eliminates parts of the malodor response pattern. This would most likely be achieved through receptor antagonism. Adaptation of response elements shared by malodor and masking odor might also contribute, but because it varies with duration of odor exposure it provides less stable suppression of elements of the malodor response pattern. In practical terms, however, the most effective masking odors will have a combination of blocking and masking effects. They will produce novel response patterns that combine strongly responding elements absent from malodor response patterns with simultaneous antagonism of key elements of malodor response patterns.
The presently-disclosed subject matter includes a method of suppressing perception of smoke or vapor odor from an inhalation-based nicotine delivery device and/or of reducing an urge to use an inhalation-based nicotine delivery device, which involves exposing a subject to a composition comprising an agent for masking the odor of 1-pentanethiol, an agent for masking the odor of guaiacol, or combinations thereof.
In some embodiments of the method disclosed herein, the agent for masking guaiacol is methyl-2-methylbutyrate and the agent for masking 1-pentanethiol is citronellal. In some embodiments of the method, the composition comprises methyl-2-methylbutyrate and citronellal.
In some embodiments, exposure to the composition suppresses perception by the subject of the smoke or vapor odor, when the subject is in the presence of the smoke or vapor odor. In some embodiments, exposure to the composition reduces the urge by the subject to use an inhalation-based nicotine delivery device.
In some embodiments, the subject is a current or past smoker or vaper. In some embodiments, the subject is at risk of coming into perceptible olfactory proximity to smoke odor or flavoring odor from a tobacco-derived product or a product mimicking tobacco smell or flavor.
In some embodiments, the inhalation-based nicotine delivery device is a cigarette, a cigar, a pipe, or a vaping device.
The ability to suppress perception of cigarette smoke odor has relevance to health as an adjunct to existing smoking cessation treatments because cigarette smoke odor increases the urge to smoke in both current and former smokers. Accordingly, in some embodiments of the method, the exposure involves placing a composition in perceptible olfactory proximity to the subject. In some embodiments, the composition is formulated to be worn by the subject, such as in a lotion, a gel, a topical semi-solid, or a liquid, such as a sprayable liquid. In some embodiments, the composition is formulated to be dispersed into the environment of the subject, such as in a diffusible liquid.
Exposure to, including wearing the composition decreases the ability of cigarette smoke odor to trigger the urge to smoke. The composition can be worn, for example, the same way one would wear a cologne, perfume, or fragrant lotion. For another example, the odorant(s) could be carried as a lotion, oil (roller applicator), or semi-solid (like lip balm), and sampled acutely when cigarette smoke odor is anticipated or encountered.
In some embodiments, the composition is provided in a wearable item, which places the composition in perceptible olfactory proximity to the subject. Examples of such wearable items include, but are not limited to the following.
In some embodiments, the wearable item is an adhesive patch. These can be infused with the composition. The patches can be made from a porous material that slowly releases the odorant over time. They can be designed to be attached to clothing, backpacks, or even directly onto the skin.
In some embodiments, the wearable item is jewelry. Necklaces or bracelets, for example, can be designed with small compartments or porous beads that hold the composition. These compartments can be made from materials like lava stones or specially designed metals that absorb and slowly diffuse the odorant.
In some embodiments, the wearable item is clothing, which can be infused with composition in a number of ways. For example, one option is to impregnate the fabric with microcapsules containing the composition. These microcapsules can break upon friction, gradually releasing the odorant. Another method is to apply a finishing treatment to the clothing that contains the composition, which can be designed to withstand a certain number of washes. In some embodiments, the clothing is a hat, headband, bandana, or scarf. Such items can be designed with built-in compartments or bands that can be infused with the composition. In some embodiments, such items can be made from absorbent materials that can be readily infused with the composition.
In some embodiments, the wearable item is a device equipped with a refillable cartridge containing the composition. For example, such a device could be a wristband having a refillable cartridge. Such a device could periodically release small amounts of the composition, placing the composition in perceptible olfactory proximity to the subject.
In some embodiments, the composition is formulated to be delivered to an environment using a diffuser. Examples of such diffusers include, but are not limited to the following.
In some embodiments, the diffuser is an ultrasonic diffusers. Such diffusers use ultrasonic vibrations to turn the composition into a fine mist that is then dispersed into the air. Such diffusers allow for effective dispersion of the composition and its odorant, without heating or burning oil components of the composition.
In some embodiments, the diffuser is a nebulizing diffusers. These diffusers work by using pressurized air to disperse a fine mist of the composition into the air. This method is highly efficient in dispersing a strong concentration of oil-based compositions, making it suitable for larger spaces.
In some embodiments, the diffuser is an evaporative diffuser or a fan diffuser. Such diffusers are simple devices where the composition is placed onto a pad or filter and is then evaporated into the air, optionally with the help of a fan. Such devices are simple and cost-effective.
In some embodiments, the diffuser is a heat diffusers. Such diffusers use heat, produced for example by electric means or from a candle, to warm and evaporate the composition. Such devices can be simple and cost-effective.
In some embodiments, the diffuser is a smart diffuser. In this regard, the diffuser is integrated with technology, such that it can be controlled through a smartphone or smart home system application. Features that can be offered include, for example, scheduling, remote activation, and control over the intensity of the diffusion, and monitoring of air quality with associated diffusion adjustment.
In some embodiments, and with reference to the description above related to wearable items, the diffuser can be a wearable personal diffusers. Such diffusers can be selected from among those described above, and are designed to be small, portable devices that can be worn around the neck or clipped to clothing. They release a small amount of composition, providing odorant within the personal space of the subject.
It is contemplated that the effectiveness of the odorants, as disclosed herein, stems from two different but complementary activities: (1) direct antagonism of some receptor proteins activated by cigarette smoke odor; and (2) distracting and complicating effects of perception of the suppressive odors, via the receptors these odors normally activate. The ability of odorants to act simultaneously as agonists at some receptors and antagonists at other receptors is common. Indeed, humans have about 400 of these odorant receptor proteins.
In addition to masking effects, which overpower an unwanted odor, compositions and methods of the presently-disclosed subject matter make making use of antagonism of receptor proteins critical for perceiving cigarette smoke odor. Antagonist effects do not suffer adaptation/desensitization, making them a much more lasting and stable way to interfere with perception of odors.
While the terms used herein are believed to be well understood by those of ordinary skill in the art, certain definitions are set forth to facilitate explanation of the presently-disclosed subject matter.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the invention(s) belong.
All patents, patent applications, published applications and publications, sequences, databases, websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety.
Where reference is made to a URL or other such identifier or address, it understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.
As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. (1972) 11(9):1726-1732).
Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently-disclosed subject matter, representative methods, devices, and materials are described herein.
The present application can “comprise” (open ended) or “consist essentially of” the components of the present invention as well as other ingredients or elements described herein. As used herein, “comprising” is open ended and means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended unless the context suggests otherwise.
Following long-standing patent law convention, the terms “a”, “an”, and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a cell” includes a plurality of such cells, and so forth.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter.
As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, in some embodiments ±0.1%, in some embodiments ±0.01%, and in some embodiments ±0.001% from the specified amount, as such variations are appropriate to perform the disclosed method.
As used herein, ranges can be expressed as from “about” one particular value, and/or to “about” another particular value. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
As used herein, “optional” or “optionally” means that the subsequently described event or circumstance does or does not occur and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, an optionally variant portion means that the portion is variant or non-variant.
The presently-disclosed subject matter is further illustrated by the following specific but non-limiting examples. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the present invention.
Studies designed for identification of effective masking odors through logical design are disclosed herein. A convergence of in vivo, ex vivo, and in vitro evidence demonstrates that many odorants act as antagonists at some ORs even while acting as agonists at other ORs. This commonality of odorant antagonism argues that antagonists specific for every malodor should exist. Screening for such antagonists can be conducted using physiological approaches, especially heterologous expression studies that screen odorants for antagonism of human odorant receptors responsive to a malodor, or more directly through psychophysical measurement of suppression of perception of malodors in human subjects. Odorant antagonism will have a peripheral effect on perception distinct from any central nervous system effect. Central and peripheral effects of interacting odorants on odor perception can be discriminated via split-nostril experiments. Odors delivered simultaneously to different nostrils (dichorhinic mixtures) can only interact at the central nervous system whereas odors delivered together to the same nostril (physical mixtures) can interact at both the olfactory epithelium and the central nervous system. Perceptual effects that are equal when two odors are delivered to the same and different nostrils result from central interaction mechanisms. Effects specific to delivery to the same nostril must be due to a peripheral mechanism, most often by receptor antagonism, while effects specific to delivery to separate nostrils must have a central mechanism.
Two odorants were identified as being the most important malodor components of both cigarette smoke and a simplified artificial mimic of cigarette smoke odor: 1-pentanethiol and guaiacol. Psychophysical methods were used to identify candidate antagonist odorants and determine whether they suppressed perception of 1-pentanethiol and guaiacol. As disclosed herein, citronellal and methyl-2-methylbutyrate suppress perception of these cigarette smoke malodors, respectively, only when applied as physical mixtures to the same nostril, demonstrating that this effect occurs at the olfactory periphery.
Odorants and their sources are listed in Table 1.
Healthy, non-pregnant volunteers in the age range of 18-60 years were recruited in the Lexington, K Y and Philadelphia, PA areas. Subjects were paid $20 per session. Subjects were allowed to participate in multiple experiments.
In all experiments each subject was presented with odor samples in a unique random order. Subjects were instructed to take a single inhalation of each sample. Samples were separated by rest periods of at least 50 sec to minimize adaptation. Target odorants (1-pentanethiol or guaiacol) were sampled thrice by each subject prior to the initiation of an experiment.
Dilutions (0.1-, 0.01-, 0.001-, and 0.0001-fold) of candidate masking odorants and the key cigarette smoke odorant 1-pentanethiol were prepared in dimethyl sulfoxide. Subjects (5 male and 7 female) sniffed 0.4 ml volumes absorbed in cotton balls from 0.8 ml brown glass vials and rated intensity on a scale of 1-10. Dilutions that gave average intensities in the range of 4-5 were selected for screening tests in which subjects rated intensity on a scale of 1-100 using a paper form. Subjects also rated whether the overall odor of each sample was pleasant or unpleasant (a forced-choice test).
Dilutions of odorants (0.1-, 0.01-, 0.001-, and 0.0001-fold) were prepared in 10 ml of mineral oil in 250 ml brown Boston round bottles. To mimic the conditions of split-nostril testing, each dilution bottle was paired with a bottle containing 10 ml of mineral oil, with both bottles connected to the same Teflon nozzle. Control samples consisted of pairs of bottles containing 10 ml of mineral oil connected to a Teflon nozzle. Subjects simultaneously sniffed from two nozzles, either an odor dilution through one nostril and a control through the other nostril, or controls through both nostrils. Each subject (n=7-9) sniffed a unique random order of dilutions, rating intensity on a scale of 1-10. Dilutions that gave average intensities in the range of 4-5 were selected.
In preliminary screening only physical mixtures were tested. Air mixing was achieved by attaching pairs of 250 ml brown Boston round bottles, one containing the candidate antagonist odorant and the other the target odorant, to a single nozzle. Controls consisted of pairs of bottles, each containing 10 ml of mineral oil, connected to the same Teflon nozzle. Subjects simultaneously sniffed from two nozzles, either a physical mixture through one nostril and the control through the other nostril, or controls through both nostrils. Each sample was repeated so that each physical mixture was sniffed through the left and right nostrils. Each subject sniffed a unique random order of the samples, rating intensity on a scale of 1-10 using Google forms.
Subjects simultaneously sniffed from two pairs of bottles, one pair per nostril. Treatment samples included no odorant controls and target odorants (1-pentanethiol or guaiacol) presented alone or mixed in air with masking odorants. Subjects experienced every sample four times, balanced so that pairings of odors were given twice per nostril, with the exception of the no odor control (10 ml of mineral oil in each bottle), which was presented twice. Subjects rated intensity on a gLMS scale (0-100) via a graphical user interface on a computer, followed by rating pleasantness on a linear scale of −10 to +10. Redjade software was used to produce unique random orders for each subject and to collect intensity and pleasantness ratings. Exclusion criteria were ratings of 0 on >25% of treatments (to exclude hyposmic subjects) and a Pearson correlation coefficient of <35% on test-retest across all treatments.
Cigarette smoke is a commonly encountered odor considered offensive by many non-smokers. In addition, it has a negative impact on human health. For most current and former smokers encountering cigarette smoke odor increases the urge to smoke. Cigarette smoke contains hundreds of volatile chemicals that trigger olfactory responses (odorants) but like many complex odors its percept can be evoked using a much smaller set of odorants. The most critical odorants for perception of this simplified artificial mimic of cigarette smoke odor are 1-pentanethiol and guaiacol.
Seventeen (17) odorants commonly used as general masking odors or previously tested as cigarette additives designed to improve the perceived pleasantness of cigarette smoke were screened. Most of these odorants had significant effects, with citronellal having the strongest effect (
Citronellal Interacts with 1-Pentanethiol in the Periphery
To discriminate peripheral versus CNS odor interaction effects a split-nostril experiment was performed where odorants delivered simultaneously to different nostrils (dichorhinic mixture) can only affect perception via central nervous system (CNS) circuits versus odorants delivered together to the same nostril (physical mixture) where they can affect perception via both peripheral effects and central effects (
Citronellal was tested, the most effective masking odor in the preliminary experiment, and pentanol was tested as a control that had no effect in the preliminary experiment. When delivered to different nostrils, citronellal did not affect the perceived intensity of 1-pentanethiol. However, citronellal reduced the perceived intensity of 1-pentanethiol when applied as a physical mixture to the same nostril (
While there was no significant difference between males and females in any of the treatments (
Unlike nearly every other odorant in the preliminary screen pentanol had no effect on perception of 1-pentanethiol (
Like 1-pentanethiol, guaiacol is a key odorant in cigarette smoke and is one of the most important components of a simple mimic of cigarette smoke odor. Eight (8) odorants were selected as candidates to suppress perception of guaiacol and a preliminary screen was conducted using physical mixtures of guaiacol with these candidates. This screen identified promising effects from four of the tested odorants (
No gender differences in the effects of candidate masking odorants on perception of guaiacol were found (
Masking Odor Pleasantness Often Correlates with Interaction Effects
In the preliminary screen of masking odorants against 1-pentanethiol the average pleasantness correlated strongly with perception of reduced amounts of 1-pentanethiol (
In the guaiacol experiment the addition of none of the masking odorants significantly altered pleasantness ratings, and there were no gender differences in perception of pleasantness (
Suppression of perception of odors by physical mixtures is believed to arise from direct antagonism of odorant receptors. The effective blocking odorants that were identified, citronellal and methyl-2-methylbutyrate, are not structurally similar to the targeted malodors, 1-pentanethiol and guaiacol, respectively. This argues that noncompetitive antagonism acting via allosteric mechanisms, rather than competitive antagonism, mediates these cases of suppression of perceived intensity of odorants. Consistent with this interpretation, other types of G-protein coupled receptors are well-known to have multiple sites where ligand binding can affect function. The data argue that odorant receptors may prove to be particularly susceptible to allosteric mechanisms mediating odorant interactions. Evolutionary pressure to expand and diversify the odorant receptor repertoire in order to keep pace with chemical evolution and the great structural diversity of odorant molecules seems likely to have overwhelmed selection against allosterically-mediated interactions and high ligand specificity in general.
The mixture where competitive antagonism was most likely to occur due to highly similar chemical structures, the physical mixture of 1-pentanol and 1-pentanethiol, did not result in any reduction in the perceived intensity of 1-pentanethiol. Instead, dichorhinic mixture of these odorants, which differ by a single atom, revealed an additive effect mediated centrally. It is contemplated that this close structural similarity results in receptor response patterns that overlap enough to evoke greater activity in the central circuit responsible for the perception of 1-pentanethiol when the two odorants are presented simultaneously to different nostrils.
Identified herein are odorants that suppress perception of two key odorants in cigarette smoke. These odorants act only when mixed physically, arguing that they are antagonists at odorant receptors responsive to the cigarette smoke odorants. These results predict an ability to suppress perception of cigarette smoke, which is desirable as an adjunct for smoking cessation given the ability of the odor of cigarette smoke to increase the urge to smoke in both current and former smokers.
OR10G4 is a human odorant receptor responsive to guaiacol when expressed heterologously in cultured cells. In addition, decreased sensitivity to guaiacol is associated with certain variant OR10G4 alleles and this predicts that OR10G4 is the guaiacol-sensitive receptor most likely to be antagonized by methyl-2-methylbutyrate. If so, when the dose-response relationship of OR10G4 to guaiacol is measured in cultured cells when methyl-2-methylbutyrate is present, the data will reflect that the maximum response decreases (reduced efficacy), that higher concentrations are needed to evoke responses, or both.
Methodologically, the activity of many odorant receptors (humans have 400 of these receptors) can be measured in vitro in certain cultured cells (HANA3A cells). Odorant receptors transduce odorant binding into production of cAMP (cyclic 3′, 5′-adenosine monophosphate) in the cytoplasm, which can be measured in real time using the Glosensor assay (Promega). In this assay the amount of cAMP determines the level of expression of firefly luciferase and therefore the level of luminescence once a luciferase substrate is provided. For each well of a 96-well plate, 10 μg of pGlosensor, 5 μg of RTP1s and 75 μg of Rho-tagged OR10G4 plasmids are transfected 18 to 24 h before odorant stimulation. Wells are then injected with 25 μL of Glosensor substrate and incubated 2 h in the dark at room temperature in an odor-free environment. Then, odorants diluted at their desired concentrations in CD293 media supplemented with copper and glutamine, are injected at a volume of 25 μL into each well and luminescence is recorded for 20 cycles of monitoring. The amount of luminescence is normalized to basal activity and to the level of luminescence in wells where cells are transfected with empty vector responses.
Once an odorant receptor highly sensitive to 1-pentanethiol is identified, the same test can be conducted for direct proof that citronellal is an antagonist of this receptor's responses to 1-pentanethiol.
Blockers of perception of key odorants in cigarette smoke, and especially antagonists of odorant receptors responsive to these key odorants, will reduce perception of cigarette smoke odor. Given that cigarette smoke odor increases the urge to smoke in both smokers and former smokers, these blockers and antagonists will decrease the ability of cigarette smoke odor to increase the urge to smoke. This will be tested by exposing current smokers to real cigarette smoke odor in the presence and absence of two types of other odors, mixtures of the blockers (citronellal and methyl-2-methyl butyrate) and an irrelevant odor. The urge to smoke will be measured using a relative reinforcing efficacy method (an objective measure) and a self-reported ratings of the urge to smoke (a subjective measure).
Methodologically, a way to provide consistent amounts of real cigarette smoke odor without any visual cue (i.e., no visible smoke) both alone and mixed with other odors has been developed. Each smoker is presented with the odor samples in a unique random order, with 5 min rest periods between samples. They rate their urge to smoke subjectively on a scale of 0-100 at 30 sec after sniffing an odor and then immediately score the number of cigarettes they would buy at that moment with their own funds at each of 19 prices ranging from $0 to $1,120 per cigarette (a relative reinforcing efficacy test). The critical comparisons in both measurement methods are those between the measures made after cigarette smoke odor alone versus cigarette smoke odor plus blocking odor.
Blockers of perception of key odorants in cigarette smoke that reduce perception of cigarette smoke odor are useful as adjuncts to existing smoking cessation treatments. Because wearing odors is common, these blocking odors, which are pleasant, can be incorporated into pleasant-smelling odor mixtures and applied directly as perfumes, colognes, or lotions—or instead incorporated into necklaces, pins, or other wearable items (such as nicotine patches). Because they work as blockers or antagonists, their efficacy is not decreased by the presence of additional pleasant odorants. These blocking odors could be worn continuously or only when encounters with cigarette smoke are anticipated.
Methodologically, patients undergoing smoking cessation treatments will be provided with either the mixture of the blocking odors or a mixture of irrelevant odors to wear continuously during waking hours over the period of their treatment. The outcome measure will be the rate of abstinence at 3 months and 6 months after onset of treatment.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, including the references set forth in the following list:
It will be understood that various details of the presently disclosed subject matter can be changed without departing from the scope of the subject matter disclosed herein. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.
This invention was made with government support under grant numbers R01 DC014468 and K18DC020155 awarded by the National Institutes of Health. The government has certain rights in the invention. This invention was made with government support under grant number R01 DC014468 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 63454247 | Mar 2023 | US |
