Elsevier

Drug Discovery Today

Volume 16, Issues 3–4, February 2011, Pages 119-131
Drug Discovery Today

Review
Foundation
Phenothiazine: the seven lives of pharmacology's first lead structure

https://doi.org/10.1016/j.drudis.2011.01.001Get rights and content

Rooted in the early days of organic dye chemistry, the phenothiazine structure and its derivatives have since held a prominent place in pharmacology and biomedicine. Initially used for histochemical stains of plasmodia by Paul Ehrlich, anthelmintic and antibiotic properties of phenothiazines were globally exploited in the 1930s and 1940s. Clinical use of N-substituted phenothiazines as antihistaminics (1940s), sedatives and antipsychotics (1950s) followed and continues to this day. Recently, interest in these structures has re-emerged for a variety of fascinating features in relation to neurodegenerative disease, spearheaded by the unique redox chemistry of phenothiazine – arguably the most potent chain-breaking antioxidant ever identified.

Introduction

What makes a chemical compound a pharmaceutical lead structure? If it is the recurrence, over more than a century, of medical applications against an ever-expanding spectrum of severe disorders, with all drugs based on the same chemical core, then phenothiazine is probably not only the first but also the most promiscuous lead structure of the 20th century.

Starting their ‘career’ as putative antimalarials in the late 1880s in the laboratory of one of the most eminent physicians ever – Paul Ehrlich – phenothiazines were globally applied to livestock and humans in the middle of the 20th century – as an anthelmintic saving uncountable lives [1]. In France, a small group of researchers at Rhône-Poulenc Laboratories developed derivatives of phenothiazine with antihistaminic effects, culminating in the introduction in 1950 of promethazine for anesthesia, and many other applications ranging from allergy to seasickness [2]. Shortly afterwards, chemical creativity led to the advent of chlorpromazine, which was administered, for a serendipitously discovered CNS effect, to schizophrenic, agitated and hyperactive psychiatric patients [2]. Antipsychotics with a phenothiazine core were unrivalled for almost 40 years, and they are essential for the clinical treatment of psychiatric disorders to this day. The World Health Organisation (WHO) List of Essential Medicines of 2009 continues to name two phenothiazines: chlorpromazine and fluphenazine, together with haloperidol, as the three indispensable drugs for the treatment of psychotic disorders [3]. In fact, the advent of the phenothiazines is widely thought to mark the beginning of biological psychiatry.

The redox activity of phenothiazine and of many congeners had already been described in the 1940s, but primarily related to technical applications in the engineering industry [4]. In the past two decades, with increasing knowledge on the role of oxidative stress in many degenerative human pathologies, interest in redox-active agents and antioxidants as potential therapeutics has recurrently peaked. Because there is growing evidence of a causal involvement of oxidative stress not only in atherosclerosis and diabetes but also in various neurodegenerative disorders, the investigation of phenothiazine, methylene blue and their derivatives in the treatment of Parkinson's and Alzheimer's diseases is probably one of the most fascinating avenues of current-day drug discovery (Fig. 1).

Section snippets

Measure for measure – the inauguration of methylene blue as a histochemical dye

Stimulated by the progress and commercial importance of aniline dyes in the 19th century, the German chemist Heinrich August Bernthsen of Heidelberg started to investigate aniline-based aromatic compounds such as methylene blue 1 to elucidate their chemical structure (Figure 2, Figure 3). In 1885, he correctly described the constitution of this dye, two years after he had first synthesized phenothiazine 3 itself by vigorous heating of diphenylamine with elemental sulfur [5]. By 1889, he became

The passionate pilgrim – the discovery of a wide spectrum of antimicrobial activities in phenothiazine and the diverse attempts to exploit them

In an early systematic drug screening of sulfur-containing substances for insecticidal activity, Campbell et al. noted that phenothiazine itself had a significant effect against culicine mosquito larvae at concentrations of 1 ppm [15]. At about the same time, Howard et al. had observed similar effects during their experiments with Mexican bean beetles [16]. Hence, phenothiazine bioactivity was apparently not restricted to single-celled organisms such as plasmodia. For comparison, DDT

As you like it – phenothiazine-containing worm chocolate and the large impact of phenothiazine's anthelmintic properties on 20th century medicine

Whereas none of the antimicrobial activities of the parent compound phenothiazine 3 has found widespread exploitation in the clinic, there is one indication for which it became world-famous: its anthelmintic effect. At the end of the 1930s, veterinarians spearheaded the field and described in diverse publications the oral administration of phenothiazine to pigs, sheep and other livestock. In 1938, Harwood et al. showed that the chemical eradicated ascarids and nodular worms from swine [30]

The taming of the shrew – how playing with the single reactive site of phenothiazine entailed an array of most precious drugs within just a few years

On the basis of Ehrlich's work with the putative antimalarial methylene blue, French researchers working with Paul Charpentier at Rhône-Poulenc Laboratories in Paris engaged in investigations of nitrogen-substituted derivatives of phenothiazine in the 1940s, one of them was the compound promethazine 5 (Phenergan, Figure 3, Figure 4) 2, 42. Although no significant antimalarial efficacy was detected, these novel compounds were tested for other commercially interesting activities, among which

The tempest – the introduction of chlorpromazine into psychiatry empties the wards of the lunatic asylums

Laborit had shared chlorpromazine 6 with psychiatric colleagues working in Paris because he speculated that the centrally sedating effects might be of value in the treatment of psychotic patients. In treating these patients with exceptional success [54], Jean Delay and Pierre Deniker found that chlorpromazine was not only a potent sedative but also literally an anxiolytic and antipsychotic drug 2, 53, 54, 55, 56, 57, backed by animal studies demonstrating that chlorpromazine blocked certain

The winter's tale – the unique redox activities of the phenothiazines and their translation from the engineering world into biomedicine

Unnoticed by the physicians prescribing phenothiazine as an anthelmintic and using it as a toolkit for the synthesis of an ever increasing number of biogenic amine receptor modulators, phenothiazine had already begun its second ‘career’ in the engineering world. Chemists and engineers noted the exceptional ease with which phenothiazine 3 served as a hydrogen donor in free-radical chain-reactions, thereby acting as a chain-breaking antioxidant. By the end of the 1940s Charles Murphy et al. had

All's well that ends well – on the rise of methylene blue and other phenothiazines as experimental agents to treat neurodegenerative disease

Tying in on earlier work on technical lipid peroxidation [96], Melvin Yu et al. from Eli Lilly laboratories reported, in 1992, that N-unsubstituted phenothiazine compounds were potent lipid peroxidation inhibitors in isolated brain lipids, and cytoprotective agents in neuronal cell culture, and they explained this property with the low oxidation potential and the high lipophilicity of these compounds [86]. In an in vivo approach of global and focal cerebral ischemia in rats, Yu et al.

Acknowledgements

The authors would like to thank J. Mocko for providing images of phenothiazine-treated C. elegans, M. Plenikowski for generating graphical illustrations on the actions of methylene blue, and M. Schreckenberger and C. Behl for their support. The authors’ experimental work on phenothiazines is supported by the Neuro Graduate School and the Interdisciplinary Research Centre for Neurosciences of the University of Mainz.

Maike J. Ohlow did her studies in pharmacy at the Johannes Gutenberg University (JGU) in Mainz, Germany, earning her State Certificate and Board Approval in 2006. After an internship at the Pharmaceutical Core Facilities of JGU Medical Center, she embarked on her experimental PhD thesis project aimed at the rational design of novel, blood–brain barrier-permeable and neuroactive antioxidants in a joint affiliation with the Department of Nuclear Medicine and the Institute for Pathobiochemistry of

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    Maike J. Ohlow did her studies in pharmacy at the Johannes Gutenberg University (JGU) in Mainz, Germany, earning her State Certificate and Board Approval in 2006. After an internship at the Pharmaceutical Core Facilities of JGU Medical Center, she embarked on her experimental PhD thesis project aimed at the rational design of novel, blood–brain barrier-permeable and neuroactive antioxidants in a joint affiliation with the Department of Nuclear Medicine and the Institute for Pathobiochemistry of JGU Medical Center. Her broader research interests comprise neurodegeneration and the origins of age-related brain disease as well as current and past strategies of neuropharmacological drug development.

    Bernd Moosmann studied biochemistry at the Free University of Berlin, Germany. Following his PhD thesis at the Max Planck Institute of Psychiatry in Munich, he went to the Sanford-Burnham Institute for Medical Research in La Jolla, CA, to investigate mechanisms of neurodegeneration in the developing brain. In 2004, he was recruited to the Institute for Pathobiochemistry of the Johannes Gutenberg University and Medical Center in Mainz. His research interests focus on oxidative stress, neurodegeneration and aging, and on understanding how fundamentals of molecular evolution may explain modern biochemical and disease processes. His special avocation is evidence-based medicine and the transfer of redox biochemical knowledge into the clinic.

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