Phenothiazines: From Coal-Tar Dyes to Chlorpromazine

Many of the great medicines of the past two centuries began with a plant: aspirin with willow bark, digoxin with foxglove, quinine with the bark of the cinchona tree, morphine with the opium poppy. Chlorpromazine, the drug Henri Laborit carried from the operating theatre into psychiatry in 1952, is not one of them. It has no plant source at all. It is a wholly synthetic molecule, and its family tree runs back not to a garden or a rainforest but to the dye works of nineteenth-century Germany, where chemists turned the black, sticky residue of coal-gas production into brilliant colours for cloth.

This page follows that family tree. It starts with the coal-tar dye chemistry that produced the three-ringed phenothiazine skeleton, moves through methylene blue and Paul Ehrlich’s malaria experiments, the phenothiazines used against worms, germs and malaria, and the antihistamines of the 1940s, and then looks at what a single chlorine atom and a longer side chain changed. It sets chlorpromazine beside its true plant-derived contemporary, reserpine from the Rauwolfia shrub, and explains what later research found about how chlorpromazine works: the discovery that it blocks the brain’s dopamine receptors, its many other receptor effects, and the antioxidant chemistry of the phenothiazine ring. The surgical and psychiatric discovery story and the drug’s later history each have their own page in this wing.

Table of Contents

  1. 1. No Plant, but a Dye: Where Chlorpromazine Came From
  2. 2. Coal Tar and the Phenothiazine Ring
  3. 3. Methylene Blue and Paul Ehrlich
  4. 4. Phenothiazines Against Worms, Germs and Malaria
  5. 5. The Antihistamine Branch: Fenethazine and Promethazine
  6. 6. One Chlorine Atom: The Chemistry of RP 4560
  7. 7. A Plant-Derived Contemporary: Reserpine from Rauwolfia
  8. 8. How Chlorpromazine Acts: The Dopamine Discovery
  9. 9. Many Receptors, Many Effects
  10. 10. Phenothiazine as an Antioxidant
  11. Key Research Papers
  12. Connections

1. No Plant, but a Dye: Where Chlorpromazine Came From

It is worth saying plainly at the start, because the question comes up so often with old medicines: chlorpromazine was never extracted from a plant, a mould or an animal, and no natural product was ever found that it copies. It was designed and made in a laboratory by the chemist Paul Charpentier at the French drug company Rhône-Poulenc in December 1950, coded RP 4560, and screened in animals by the pharmacologist Simone Courvoisier before Laborit tried it in surgery. Every step of its making was synthetic chemistry.

Its “natural” ancestry is therefore chemical rather than botanical. The historians Francisco López-Muñoz and colleagues, in their 2005 history of the drug’s discovery, trace it to the German coal-tar dye industry of the late nineteenth century. Coal tar is itself a natural material in one sense — it is what is left behind when coal, the fossilised remains of ancient forests, is heated to make gas and coke — but the molecules chemists pulled out of it and rebuilt were new to medicine. Out of that industry came a ring-shaped molecule called phenothiazine, and out of phenothiazine, over about seventy years, came dyes, stains, antiseptics, worm treatments, antimalarials, antihistamines and finally the first modern antipsychotic.

The pharmacologists Michael Ohlow and Bernd Moosmann have called phenothiazine “pharmacology’s first lead structure” and described its “seven lives” — the many times the same chemical skeleton was picked up and turned to a new medical use. Chlorpromazine was only one of those lives, but it was the one that changed psychiatry. The sections below follow the lives in order.

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2. Coal Tar and the Phenothiazine Ring

In the middle of the nineteenth century, coal gas lit the streets of Europe’s cities, and the gasworks left behind enormous quantities of coal tar. Chemists discovered that this unpromising waste was a rich source of aromatic compounds — benzene, aniline, naphthalene, anthracene — and that these could be rebuilt into synthetic dyes far cheaper and brighter than the plant and insect colours they replaced. Germany became the centre of this new industry, and its chemists became the most skilled in the world at reshaping ring-shaped molecules.

López-Muñoz and colleagues name three German chemists in the background to phenothiazine. Carl Graebe and Carl Liebermann were leaders of the synthetic dye chemistry of the period, famous for making the red dye alizarin — until then obtained from the madder root — from coal-tar anthracene. August Bernthsen is credited with preparing the parent phenothiazine molecule itself in the 1880s, in the course of working out the structure of the new sulfur-containing dyes such as methylene blue.

What the ring looks like

Phenothiazine is made of three rings fused side by side. The two outer rings are ordinary benzene rings, six carbon atoms each. The middle ring joins them through two bridging atoms: a nitrogen on one side and a sulfur on the other (the name comes from pheno- for the benzene rings, thi- for sulfur and -azine for the nitrogen-containing ring). The molecule is not flat but folded slightly along the line between the nitrogen and the sulfur, like a partly opened book.

Two features of this skeleton mattered for everything that followed. First, the nitrogen in the middle ring has a free position where chemists could attach a side chain, and changing that side chain changed what the drug did in the body. Second, the outer rings have positions where a single extra atom — such as chlorine — could be added. Together these two “handles” gave chemists a way to tune the same skeleton into very different medicines.

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3. Methylene Blue and Paul Ehrlich

The first member of the family to reach medicine was a dye: methylene blue, a deep blue phenothiazine compound made in the German dye industry in the 1870s for colouring textiles. It entered the laboratory as a stain. The young German physician-scientist Paul Ehrlich was fascinated by the way certain dyes coloured some tissues and some microbes but not others, and he used methylene blue among many other dyes in his studies of blood cells, nerves and bacteria.

That selective staining led Ehrlich to a bold thought. If a dye could pick out a parasite and colour it while leaving the surrounding cells pale, perhaps a dye could also attack the parasite while sparing the patient. Methylene blue stained the malaria parasite, Plasmodium, strongly. According to the historians W. W. Shen and Walter Sneader, in 1891 Ehrlich began investigating methylene blue as a treatment for malaria, and he and a colleague reported treating malaria patients with it. It was one of the first times a synthetic chemical had been used against a specific infectious organism, and it became a founding example of Ehrlich’s idea of the “magic bullet” — a chemical aimed at a germ.

Methylene blue never displaced quinine, the old cinchona-bark remedy, as the main malaria treatment, but its significance for this story is the chemistry it carried. Sneader’s 2002 account of chlorpromazine’s fiftieth anniversary begins precisely here: methylene blue led chemists to further phenothiazine antimalarials, those led to the antihistamines, and the antihistamines led to chlorpromazine. Methylene blue itself had a long later career of its own, which the site covers on its Methylene Blue page and its history page on Ehrlich, malaria and the phenothiazines; Ehrlich’s wider work has its own wing.

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4. Phenothiazines Against Worms, Germs and Malaria

In the half-century after Ehrlich’s malaria work, phenothiazine and its relatives were tried against one infection after another. López-Muñoz and colleagues summarise this period simply: up to about 1940, phenothiazine derivatives were used as antiseptics, anthelmintics (worm treatments) and antimalarials, and they list Ehrlich, the German chemist Werner Schulemann and the American chemist Henry Gilman among the scientists associated with this work. Schulemann’s antimalarial research in the 1920s, like Ehrlich’s, took methylene blue as its starting point.

Worms

Ohlow and Moosmann describe the 1930s and 1940s as the period of phenothiazine’s anthelmintic and antibiotic uses. The plain, unsubstituted phenothiazine molecule turned out to be active against intestinal worms, and it became especially important in veterinary medicine, where it was given to farm animals to clear roundworm infections. This was the phenothiazine ring doing its job almost unmodified — long before anyone attached the side chains that would give it effects on the brain.

Germs

Phenothiazine compounds were also used as urinary and general antiseptics in the same years. Methylene blue in particular had a long run as a mild antiseptic and as a diagnostic dye. None of these uses involved the nervous system; the molecules were valued for what they did to microbes and parasites. That is part of what makes the later story surprising. The same chemical family that had been used to kill worms in sheep would, with a few changes at its edges, produce the drug that the historian Thomas Ban credits with the transformation of disturbed wards in mental hospitals.

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5. The Antihistamine Branch: Fenethazine and Promethazine

The turn towards the nervous system came through allergy research. In the late 1930s and 1940s, French pharmacologists — the circle associated with Daniel Bovet at the Pasteur Institute, together with chemists and pharmacologists such as Bernard Halpern and the chemists at Rhône-Poulenc — were searching for drugs that could block histamine, the body’s chemical alarm signal released by mast cells in allergy and injury. Bovet’s work on antihistamines would later win him the 1957 Nobel Prize in Physiology or Medicine; his story is told on the site’s Daniel Bovet page.

Several of the most effective antihistamines of the period turned out to be phenothiazines carrying a side chain on the ring nitrogen. Sneader describes fenethazine as a potent antihistamine of this kind, and notes that closely related compounds (homologues) proved to have strong anticholinergic effects — that is, they blocked acetylcholine, another of the body’s chemical messengers — and were used to treat Parkinson’s disease. One such relative, diethazine, appears in the historical record both as a drug for the trembling and stiffness of Parkinson’s disease and among the agents Laborit is reported to have tried in his early anaesthetic mixtures. The phenothiazines were already showing that they could act on the brain.

Promethazine and its drowsiness

In 1947 Rhône-Poulenc’s chemists made promethazine, a phenothiazine antihistamine with a short, branched side chain. It was a strong antihistamine, but it also made people markedly drowsy and indifferent to their surroundings. For an allergy drug that was a nuisance. For Laborit, working on surgical shock, it was the interesting part. His 1950 paper on synthetic antihistamines in surgery reported his experience with these drugs, and he came to value promethazine precisely for its effects on the central nervous system.

According to Sneader’s account, it was those central effects that prompted the next step: a deliberate request for a phenothiazine in which the action on the brain was stronger and the antihistamine action relatively weaker. The chemistry of that request is the subject of the next section.

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6. One Chlorine Atom: The Chemistry of RP 4560

When Charpentier set out to make a phenothiazine with stronger central action, he had two handles to work with: the side chain on the ring nitrogen and the free positions on the outer rings. Chlorpromazine, the compound he made in December 1950, differs from promethazine in both.

The side chain

Promethazine’s side chain links the ring nitrogen to a second, outer nitrogen through two carbon atoms with a small branch. Chlorpromazine’s side chain is a straight run of three carbon atoms ending in a dimethylamino group (a nitrogen carrying two small methyl groups). In the chemistry of the phenothiazines that change mattered a great deal: in reviews of the family’s structure–activity relationships, such as the 2019 “Classics in Chemical Neuroscience” review of chlorpromazine by Debra Boyd-Kimball and colleagues, the three-carbon chain between the two nitrogens is the arrangement associated with antipsychotic activity, while the shorter, branched chains are associated with antihistamine action.

The chlorine

The second change is the one that gives the drug its name. Chlorpromazine carries a single chlorine atom on one of the outer rings, at the position chemists number 2. The same molecule without the chlorine (promazine) had been made as well; adding the chlorine made the compound considerably more potent on the brain. The full chemical name — 2-chloro-10-(3-dimethylaminopropyl)phenothiazine — simply spells out the three pieces: the ring, the chlorine at position 2, and the three-carbon side chain on the nitrogen at position 10.

The result was what Laborit had asked for. Courvoisier’s animal tests showed strong central effects, and in February 1952 Laborit, Huguenard and Alluaume described RP 4560 as a “new vegetative stabilizer”. In the historian Thomas Ban’s translation, they reported that it produced “disinterest without loss of consciousness and with only a slight tendency to sleep”. How that observation reached psychiatry is told on the discovery page. Chemists then went on to vary the same two handles — different ring substituents, different side chains — and produced dozens of further phenothiazine antipsychotics; Shen counts roughly fifteen antipsychotics introduced in the United States and about forty worldwide between 1954 and 1975.

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7. A Plant-Derived Contemporary: Reserpine from Rauwolfia

If chlorpromazine is the synthetic side of the birth of psychopharmacology, its natural-medicine twin is reserpine. Reserpine is an alkaloid from Rauwolfia serpentina, a small shrub of South and Southeast Asia known in India as sarpagandha, whose root had a long history in traditional Indian medicine. Purified reserpine entered Western medicine in the early 1950s, first for high blood pressure, and arrived in psychiatry at almost exactly the same moment as chlorpromazine.

The two drugs were studied side by side from the start. In 1955 Jean Delay, Pierre Deniker and their colleagues at the Sainte-Anne hospital in Paris published preliminary trials of reserpine in psychiatry together with a comparison with the effects of chlorpromazine. A year earlier, the Swiss psychiatrist Hans Steck had described an extrapyramidal syndrome — stiffness, slowness and tremor resembling Parkinson’s disease — developing in the course of treatment with both drugs, an early sign that the two very different molecules shared something in how they acted on the brain. When the Lasker Foundation honoured the new drugs in 1957, it gave its clinical award to Laborit, Deniker and Heinz Lehmann for chlorpromazine, and to the American psychiatrists Nathan Kline and Robert Noce for reserpine.

Two routes to the same chemical messengers

The pairing turned out to be scientifically important. As the neurochemist Gerald Curzon described in a 1990 review of how reserpine and chlorpromazine act, working out the mechanisms of these two drugs shaped the whole history of psychopharmacology. Reserpine was found to empty nerve endings of their stores of monoamine messengers, including dopamine; the Swedish pharmacologist Arvid Carlsson’s experiments with reserpine-treated animals in the late 1950s helped establish dopamine as a brain transmitter in its own right (told on the site’s Carlsson, Greengard and Kandel page). Chlorpromazine, as the next section explains, turned out to act on the receiving side of the same dopamine system. One drug from a plant root and one from a dye works were, in the end, touching the same chemistry from opposite ends.

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8. How Chlorpromazine Acts: The Dopamine Discovery

For more than a decade after 1952, nobody knew how chlorpromazine worked. Laborit had thought in terms of the autonomic nervous system and the body’s reaction to stress; the psychiatrists described what they saw in patients. The explanation that eventually emerged came from brain chemistry, in three main steps.

1963: Carlsson and Lindqvist

In 1963 Arvid Carlsson and Margit Lindqvist reported that chlorpromazine and haloperidol (a chemically unrelated antipsychotic) increased the formation of breakdown products of dopamine and noradrenaline — 3-methoxytyramine and normetanephrine — in mouse brain. Their interpretation, as Ban summarises it, was that the drugs were blocking the receptors for these messengers, so that the brain’s nerve cells responded by releasing and turning over more of them. It was the first strong clue that antipsychotics worked by blocking the brain’s catecholamine receptors.

1975–1976: binding studies

The decisive evidence came when techniques were developed to measure drugs binding directly to receptors in brain tissue. In 1975 Philip Seeman and colleagues in Toronto published direct binding assays of brain receptors for antipsychotic drugs and dopamine, and found that the drugs’ inhibitory potencies on dopamine and haloperidol binding correlated with the doses used clinically. In 1976 Ian Creese, David Burt and Solomon Snyder at Johns Hopkins reported that dopamine-receptor binding predicted the clinical and pharmacological potencies of antischizophrenic drugs: the clinical potencies of the butyrophenones and phenothiazines matched how strongly they inhibited [3H]haloperidol binding. Seeman’s group published a parallel paper in Nature the same year relating antipsychotic drug doses to the neuroleptic/dopamine receptor.

The pattern was striking: across a wide range of drugs, the more tightly a drug bound to this dopamine receptor (later classed as the D2 type), the smaller the dose needed in patients. That correlation became the foundation of the “dopamine hypothesis” of schizophrenia and of the search for every later antipsychotic. The disease itself is covered on the site’s Schizophrenia page.

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9. Many Receptors, Many Effects

Chlorpromazine is not a precise drug. Besides dopamine receptors, it binds to receptors for several other chemical messengers, and much of its clinical character — good and bad — comes from that breadth. Boyd-Kimball and colleagues review this wide pharmacology, and the Cochrane review of fifty years of randomised trials by Clive Adams and colleagues (2005) records the effects that followed from it in practice.

Seen this way, chlorpromazine carries traces of every branch of its family history. The dye-derived ring gives it its shape, the antihistamine ancestry gives it sedation, the anticholinergic relatives of the Parkinson’s drugs echo in its dry mouth, and the chlorine and three-carbon chain give it the strong dopamine blockade that made it an antipsychotic. The longer story of its side effects, from movement disorders to jaundice and blood disorders, is told on the legacy page.

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10. Phenothiazine as an Antioxidant

One more life of the phenothiazine ring has nothing to do with dyes, germs or the brain’s receptors. The sulfur and nitrogen atoms in the middle ring make the molecule easy to oxidise — to give up an electron — and that property has two faces. Ohlow and Moosmann describe the redox (oxidation–reduction) chemistry of the phenothiazines as one of their defining features and characterise phenothiazine itself as a very potent chain-breaking antioxidant: a molecule that can stop a chain reaction of free radicals by donating an electron or hydrogen atom and forming a relatively stable radical of its own.

The same chemistry explains several practical features of the family. Methylene blue switches between a blue oxidised form and a colourless reduced form, the property that made it useful as a redox indicator and underlies its other medical uses. Chlorpromazine, too, is easily oxidised: its solutions are sensitive to light and air and darken as they oxidise, and the drug is known in the clinical record for making the skin more sensitive to sunlight. Industrial chemists also use phenothiazine as an antioxidant and stabiliser for reactive materials.

Whether this antioxidant chemistry matters for any of chlorpromazine’s effects in the body is a separate question, and Ohlow and Moosmann present it as an area of research interest rather than an established medical use. What it does show is how much chemistry was packed into the three rings that Bernthsen’s generation first drew in the 1880s: a dye, a stain, a worm treatment, an antimalarial, an antihistamine, an antipsychotic and an antioxidant, all from one skeleton born in the coal-tar dye works.

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Key Research Papers

  1. López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17(3):113-35. PubMed PMID: 16433053
  2. Ohlow MJ, Moosmann B. Phenothiazine: the seven lives of pharmacology’s first lead structure. Drug Discov Today. 2011;16(3-4):119-31. PubMed PMID: 21237283
  3. Sneader W. The 50th Anniversary of Chlorpromazine. Drug News Perspect. 2002;15(7):466-471. PubMed PMID: 12677184
  4. Shen WW. A history of antipsychotic drug development. Compr Psychiatry. 1999;40(6):407-14. PubMed PMID: 10579370
  5. Laborit H. Synthetic antihistamines in surgery. Sem Hop. 1950;26(69):3646-9. PubMed PMID: 14781932
  6. Laborit H, Huguenard P, Alluaume R. A new vegetative stabilizer; 4560 R.P. Presse Med. 1952;60(10):206-8. PubMed PMID: 14957790
  7. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500. PubMed PMID: 19300578
  8. Delay J, Deniker P, Tardieu Y, Lemperiere T. Neuroplegic medications and cures in psychiatry: preliminary trials with reserpine; comparison with the effects of chlorpromazine. Presse Med. 1955;63(32):663-5. PubMed PMID: 14395087
  9. Steck H. Extrapyramidal and diencephalic syndrome in the course of largactil and serpasil treatments. Ann Med Psychol (Paris). 1954;112(2:5):737-44. PubMed PMID: 14362101
  10. Curzon G. How reserpine and chlorpromazine act: the impact of key discoveries on the history of psychopharmacology. Trends Pharmacol Sci. 1990;11(2):61-3. PubMed PMID: 2180160
  11. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 1963;20:140-4. PubMed PMID: 14060771
  12. Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci U S A. 1975;72(11):4376-80. PubMed PMID: 1060115
  13. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192(4238):481-3. PubMed PMID: 3854
  14. Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261(5562):717-9. PubMed PMID: 945467
  15. Boyd-Kimball D, Gonczy K, Lewis B, Mason T, Siliko N, Wolfe J. Classics in Chemical Neuroscience: Chlorpromazine. ACS Chem Neurosci. 2019;10(1):79-88. PubMed PMID: 29929365
  16. Adams CE, Rathbone J, Thornley B, Clarke M, Borrill J, Wahlbeck K, Awad AG. Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials. BMC Med. 2005;3:15. PubMed PMID: 16229742

PubMed Topic Searches

  1. Phenothiazine history
  2. Methylene blue, Ehrlich and malaria
  3. Chlorpromazine and dopamine-receptor binding
  4. Reserpine and chlorpromazine history
  5. Phenothiazine antioxidant chemistry

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Connections