Shape theory of olfaction
In 1949, R.W. Moncrieff published an article in American Perfumer called "What is odor: a new theory," which used Linus Pauling's notion of shape-based molecular interactions to propose a shape-based theory of odor. This superseded the older vibration theory of olfaction and remains the mainstream theory, in both commercial fragrance chemistry and academic molecular biology. Three years after Moncrieff proposed the theory, John Amoore speculated further that the over ten thousand smells distinguishable by the human olfaction system resulted from the combination of seven basic primary odors correlating to odor receptors for each, much as the spectrum of perceived colors in visible light is generated by the activation of three primary color receptors. Amoore's seven primary odors included sweaty, spermous, fishy, malty, urinous and musky. His most convincing work was done on the camphoraceous odor, for which he posited a hemispherical socket in which spherical molecules, such as camphor, cyclooctane, and naphthalene could bind.
When Linda Buck and Richard Axel published their Nobel Prize winning research on the olfactory receptors in 1991, they identified in mice 1,000 G-protein-coupled receptors used for olfaction. Since all types of G-protein receptors currently known are activated through binding of molecules with highly specific conformations, or shape, it is assumed that olfactory receptors operate in a similar fashion. Further research on human olfaction systems identified 347 olfactory receptors.
The most recent shape theory, also known as odotope theory or Weak Shape Theory, holds that a combination of activated receptors is responsible for any one smell, as opposed to the older model of one receptor, one shape, one smell. Receptors in the odotope model recognize only small structural features on each molecule, and the brain is responsible for processing the combined signal into an interpreted smell. Much current work on shape theory focuses on neural processing, rather than the specific interaction between odorant and receptor that generates the original signal.
Numerous studies have been conducted to elucidate the complex relationship between the shape of an odorous molecule and its perceived smell character, and fragrance chemists have proposed structure models for the smells of amber, sandalwood, and camphor, among others.
A study by Leslie B. Vosshall and Andreas Keller, published in Nature Neuroscience in 2004, tested several key predictions of the competing vibration theory and found no experimental support for it. The data were described by Vosshall as "consistent with the shape theory," although she added that "they don't prove the shape theory."
Another study also showed that molecular volume of odorants can determine the upper limits of neural responses of olfactory receptors in Drosophila.
- Despite numerous studies, shape theory has yet to discover shape-odor relations with great predictive power.
- Similarly shaped molecules with different molecular vibrations have different smells (metallocene experiment and deuterium replacement of molecular hydrogen).
- Differently shaped molecules with similar molecular vibrations have similar smells (replacement of carbon double bonds by sulfur atoms and the disparate shaped amber odorants).
- Hiding functional groups does not hide the group's characteristic odor.
- Very small molecules of similar shape, which seem most likely to be confused by a shape-based system, have extremely distinctive odors, such as hydrogen sulfide.
- Some studies seem to show that human beings and animals can distinguish between isotopes by smell, despite their identical shapes.
- Odor descriptions in the olfaction literature correlate more strongly with their vibrational frequencies than with their molecular shape.
- Moncrieff, Robert Wighton (1949), "What is odor? A new Theory", American Perfumer 54: 453
- TWOMBLY, RENEE (2004-03-26). "The Rockefeller University - Newswire: Two Rockefeller faculty become new HHMI investigators". Retrieved 2009-06-10.
- Saberi M, Seyed-allaei (2015). "Olfactory receptors are sensitive to molecular volume of odorants". bioRxiv. doi:10.1101/013516.
- Burr, Chandler (2003). The Emperor of Scent: A Story of Perfume, Obsession, and the Last Mystery of the Senses. New York: Random House. ISBN 0-375-50797-3.
- Keller, A and Vosshall, LB. (2004). A psychophysical test of the vibration theory of olfaction. Nature Neuroscience 7:337-338. See also the editorial on p. 315. (Newsletter report, Rockefeller University Scientist).
- The Nobel Prize in Physiology or Medicine 2004. 
- Sell, Charles. (2006) On the Unpredictability of Odor. Angewandte Chemie. Volume 45, Issue 38, 6254-6261. 
- Turin, Luca, (1996). Chemical Senses. 21(6):773-791 A spectroscopic mechanism for primary olfactory reception
- Turin, Luca (2006). The Secret of Scent. London: Faber & Faber. ISBN 978-0-571-21537-9.
- Zozulya et al. (2001) "The human olfactory receptor repertoire."