Substance P Receptor Blockers (Neurokinin-1
Antagonists)

The Discovery

Act One: The Unexpected Discovery

In 1931, Swedish scientist Ulf von Euler and British pharmacologist John Gaddum were grinding up ...

In 1931, Swedish scientist Ulf von Euler and British pharmacologist John Gaddum were grinding up horse brains and intestines looking for acetylcholine. They found something else entirely — a powder that made smooth muscles contract and blood pressure drop. They called it 'Substance P,' with P standing for 'preparation' or 'powder.' For decades, no one knew exactly what Substance P was. It was just a mysterious material that caused pain and inflammation when injected into tissue. It took until 1971 for scientists to finally identify its structure: an 11-amino-acid peptide that turned out to be one of the most important pain and inflammation signals in the body.

The Breakthrough

Act Two: The Mystery Deepens

Through the 1970s and 1980s, neuroscientists mapped Substance P throughout the nervous system.

Through the 1970s and 1980s, neuroscientists mapped Substance P throughout the nervous system. They found it concentrated in pain nerve fibers, where it transmitted pain signals from the body to the brain. But Substance P wasn't just about pain. It caused blood vessels to leak fluid (creating swelling), stimulated immune cells, triggered vomiting reflexes, and played roles in anxiety and depression. Scientists identified its receptor, called NK1 (neurokinin-1), and realized that blocking this receptor might treat multiple conditions at once. The race to create NK1 receptor antagonists — drugs that block Substance P — began in pharmaceutical labs worldwide.

The Trials

Act Three: The Race Begins

Merck, Pfizer, GlaxoSmithKline, and other major companies poured hundreds of millions of dollars ...

Merck, Pfizer, GlaxoSmithKline, and other major companies poured hundreds of millions of dollars into developing NK1 antagonists. The first candidates were designed to treat chronic pain and depression. Animal studies were spectacular: NK1 antagonists eliminated pain responses and reduced anxiety-like behavior in mice and rats. Scientists were confident they had found a revolutionary new class of drugs. But human trials told a different story. NK1 antagonists failed repeatedly as painkillers. They showed inconsistent results for depression. The gap between animal models and human patients was enormous and humbling.

The Crisis

Act Four: Aprepitant Breakthrough

Just when hope was fading, Merck's NK1 antagonist aprepitant found an unexpected home.

Just when hope was fading, Merck's NK1 antagonist aprepitant found an unexpected home. Clinical trials showed it was extraordinarily effective at preventing chemotherapy-induced nausea and vomiting — one of the most dreaded side effects of cancer treatment. The FDA approved aprepitant (brand name Emend) in 2003. For cancer patients, it was transformative. Combined with other anti-nausea drugs, aprepitant virtually eliminated the severe vomiting that had made chemotherapy unbearable for millions of patients. It worked because Substance P activates the brain's vomiting center, and blocking it shut down the nausea response at its source.

The Legacy

Act Five: Expanding Power

Today, NK1 antagonists are standard of care in cancer chemotherapy suites worldwide.

Today, NK1 antagonists are standard of care in cancer chemotherapy suites worldwide. Newer versions like fosaprepitant (IV form) and rolapitant (long-acting) give doctors more options. Researchers haven't given up on other applications either. Clinical trials continue testing NK1 antagonists for alcohol dependence, post-traumatic stress disorder, and severe itching conditions. Recent studies suggest that Substance P plays a role in inflammatory bowel disease and some autoimmune conditions. The 'mysterious powder' that Euler and Gaddum found in horse brains in 1931 led to an entire pharmaceutical class that helps cancer patients endure life-saving treatment.