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Why Is It Called Substance P? The 40-Year Hunt for a Brain Peptide
Peptides usually have names that describe what they are. Substance P has a name that describes nothing at all. It was given the name of a letter because, for almost forty years, nobody knew what the material in the tube actually was.
Key takeaways
- In 1931, Ulf von Euler and John Gaddum found a substance in horse brain and intestine that contracted gut muscle and lowered blood pressure.
- The “P” is said to stand for powder, from the dried preparation they used.
- The active material could not be purified until Susan Leeman’s group isolated a peptide from bovine hypothalamus around 1970.
- Substance P is a chain of 11 amino acids with an amidated end.
- It belongs to the tachykinin family and acts on neurokinin receptors involved in pain and inflammation research.
A powder with a mystery
In 1931, von Euler, working in London with the pharmacologist John Gaddum, prepared extracts from horse brain and intestine. The dried extract made isolated gut muscle contract and lowered blood pressure in animals. They kept the dried material in a bottle labeled “P”. Accounts differ on whether the letter meant powder or preparation, but the name stuck.
The active material proved stubborn. Without modern chromatography, it could not be separated from the many other molecules in tissue, and for decades it remained a biological activity with no chemical identity. Von Euler went on to win the 1970 Nobel Prize for other work, on nerve transmitters.
Leeman’s detour
The breakthrough came in an unexpected way. In the late 1960s, Susan Leeman and her colleagues in Massachusetts were purifying a factor from bovine hypothalamus that made animals salivate. They traced the activity to a small peptide, and then noticed that its other effects matched those of the old substance P. Her team isolated it and, with Chang and Niall, worked out its sequence in 1971: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met, with the last amino acid amidated.
What the sequence told us
Eleven amino acids, with a block of basic amino acids at the front and aromatic amino acids near the end. The end of the peptide, with its amide cap, is crucial to receptor binding, an example of the principles in our post on terminal modifications. Substance P is the best-known member of the tachykinin family, named for the fast contraction they cause.
From curiosity to a drug target
Substance P is released by sensory nerves and acts on the neurokinin-1 receptor. Researchers have studied it in pain, inflammation, nausea and other signaling models. A small molecule that blocks the neurokinin-1 receptor, aprepitant, was approved in 2003 for a specific clinical use, showing that the peptide’s receptor was a valid drug target. Peptides themselves are broken down quickly, which makes them hard to use directly, as discussed in half-life engineering.
What the lab takes from the story
- A biological activity can be real long before its molecule is known.
- Purification and sequencing, such as MS/MS, turn an activity into a defined molecule.
- Short peptides often rely on end modifications for activity.
- Receptor biology matters as much as the peptide, which is why binding and functional assays like radioligand binding are used together.
The bottom line
The name Substance P is a leftover from a time when chemistry could not keep up with biology. It is a reminder that every peptide in a catalog today began as an unexplained effect. For another short inflammation-focused peptide, see our KPV overview.
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.