Adding another aroma compound can sometimes make musk easier to detect without increasing the amount of musk itself. A 2023 study found that certain aldehydes enhanced the activity of a musk-responsive odorant receptor, with changes also appearing in human odor-detection tests.
What makes this interesting is that it is not simply a matter of adding together the intensities of two odors. The study linked cell experiments with human perception to investigate how one compound changes the nasal mechanism that detects another.
Focusing on a gateway for musk detection
The study centered on the human odorant receptor OR5AN1. Receptors are proteins that detect odor molecules and transmit signals into cells. OR5AN1 responds to certain musk compounds, including muscone and muscenone.
The team first measured the concentrations at which people detected 13 structurally different musks and examined relationships in sensitivity across compounds. Similarities in sensitivity did not perfectly follow classifications based on chemical structure. However, for the group comprising muscone, muscenone, musk ketone, and musk xylene, human sensitivity corresponded with OR5AN1 responses. Comparisons of mirror-image molecules also supported the link between this receptor and detection sensitivity.
This led to a further question: if another molecule changes OR5AN1’s response, does human sensitivity to musk change too?
Screening 780 substances for combinations that enhance receptor activity
In the experiments, cultured cells expressing OR5AN1 were exposed to a low concentration of muscenone combined separately with each of 780 odorants. After testing candidates at different concentrations and comparing a further 111 related compounds, the researchers identified aldehydes with particular structures that enhanced the receptor’s response.
The effective substances shared features of carbon-chain length and double-bond position. Even among molecules of similar length, replacing the aldehyde group with an alcohol or acid group, or changing the double-bond position, did not produce the same enhancement. The result did not apply to aldehydes in general.
One compound examined in detail was (Z)-2-nonenal. Adding it allowed OR5AN1 to respond at lower musk concentrations or increased the maximum response. The pattern of change depended on the musk paired with it.
More than competition for the same site
The team explained these effects through allosteric modulation: a mechanism in which action at a site distinct from the main compound’s binding site changes how the receptor functions. Analyses of concentration–response relationships and experiments replacing parts of the receptor supported this explanation.
Changing particular receptor amino acids sometimes weakened enhancement without greatly changing the response to muscenone alone. Structural modeling and molecular docking calculations also suggested possible sites of action for the enhancing compound. These were candidates based on experiments and computation, not directly imaged structures of the actual bound complex.
The same compounds behaved differently at the corresponding mouse receptor or at other human receptors. Enhancing combinations were also found for another human receptor, OR10J5, showing that the mechanism was not restricted to OR5AN1 but did not operate uniformly across all receptors.
Modulation could also work in the opposite direction. The musk compound galaxolide suppressed OR5AN1 responses to some musks. In addition, tests of five naturally occurring OR5AN1 genetic variants showed increased responses when (Z)-2-nonenal was added, including in variants that responded poorly to musk alone. Sensitivity to individual compounds is therefore insufficient to describe responses to mixtures.
Did people also find musk easier to detect?
In the human tests, participants chose which of three containers contained added musk. All three contained the same concentration of either the enhancing compound or a comparison compound, so the background odor alone could not identify the correct answer. Concentrations of the enhancing and comparison compounds had been chosen beforehand to match their perceived intensities.
Musk concentrations were varied stepwise, and correct-response rates were adjusted for chance to compare detectability. There were 115 participants across the study, but not all 115 took part in every experiment. The enhancement tests comprised 50 sessions for muscenone and 28 for muscone, with many people participating more than once.
Both muscenone and muscone were easier to detect against a (Z)-2-nonenal background than against the comparison background of nonanal. For muscenone, mean detection probability across the tested concentration range increased from 0.34 to 0.46.
For muscone, a sensitivity measure derived from the detection curve also shifted toward lower concentrations. These concentrations refer to the liquid placed in the containers. They do not describe airborne concentrations or a multiplier for the strength of perfume applied to skin.
By contrast, another candidate that enhanced responses in cells, (E)-2-tridecenal, did not significantly change muscenone detection in people. Enhanced cellular responses and improved human detection both need to be measured directly.
Thinking about scent mixtures through how they are received
An important contribution of this study is the demonstration that odor mixtures can interact at the receptor stage, at the entrance to the olfactory system. The size of enhancement depends on the compounds, receptor, and concentration, and some combinations are suppressive.
The tests concerned specific pairings of musks and background compounds. They did not assess the liking, longevity, or diffusion from skin of finished perfumes. Nevertheless, they suggest that scent design can consider not only which ingredients are included and in what quantities, but also how molecules arriving together interact at the nose.
The research was funded internally by Firmenich, and all authors were employees of the company when it was conducted. Related patent applications were also disclosed.
Summary
Specific aldehydes modulated the activity of the musk receptor OR5AN1, and pairing musk with (Z)-2-nonenal also improved human detection of muscenone and muscone. However, another candidate enhanced cellular responses without producing a significant improvement in human detection.
The study also identified suppressive combinations and increased mixture responses in genetic variants that responded poorly to musk alone. Understanding musk perception requires looking beyond ingredient amounts to receptor types and interactions among molecules arriving together. That is the perspective this research opens up.
References
Trimmer C, et al. Allosteric modulation of a human odorant receptor. Current Biology. 2023;33:1523–1534.e4. doi:10.1016/j.cub.2023.03.016
