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September 19, 2006
By Any Other Name
There's a paper in the latest Ang. Chem. that will be of interest to everyone who's into the way that various chemicals smell. And hey, what organic chemist isn't?
It's by a flavor and fragrance chemist, who lists many tables of compounds that have very minor structural variations but completely different smells. One noteworthy example is geraniol, which is a large component of the scent of roses. Adding a methyl group next to its primary allylic alcohol coverts it to an analog with an "intense fungal odor", which I don't think I'm going to be lining to up sample any time soon. And you'd have thought that the smell of geraniol would be pretty robust - you can saturate the allylic double bond, and it's still rosy. Take that compound and substitute an aryl group for the isobutenyl on the other end - still rosy. But don't mess with that primary alcohol.
The take-home lesson is that there are no major SAR trends in odor that you can count on. A substitution that works in one series can do nothing when applied to a closely related compound, or it can take the odor off in a completely unexpected direction. That aryl-for-isobutenyl switch I mentioned, for example, isn't silent if you try it on benzylacetone (4-phenyl-2-butanone). The starting ketone smells "sweet and floral", but the corresponding methylheptenone is described as "pungent, green, herbaceous".
The reason for all this craziness is that there are hundreds of olfactory receptors, most of which appear to respond to huge numbers of compounds as agonists. (There's that induced fit again)! And it's not like the agonists all smell the same, either. There also appear to be multiple binding sites involved, and possibly other protein cofactors as well. The structural complexities are bad enough, but there are probably neural processing effects laid on top of them, which makes the author predict that "consistently accurate prediction of odors will not be possible for a very considerable time". He's quick to point out that it's not like the flavor and fragrance industry has to money to underwrite the work needed to do it, either.
Does this remind you of anything, fellow medicinal chemists? If the perception of smell is the physiological readout in this case, how different is this from all the physiological states we're trying to produce with our small drug molecules? How well do we really understand their binding, and how much can we trust our SAR models? Hey, the fragrance people have big advantages on us - they can immediately test their molecules just by sticking them under their noses, which is like a five-second clinical trial with no FDA needed. And they're still as lost as geese. A lot of the time, so are we.
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