Pioneers in pharmacology and drug discovery -  Professor Norman G Bowery

At Pharmacology 2019, the Society will host the first in a series of annual symposia to recognise pioneers in pharmacology and drug discovery. The first recipient of this accolade will be in memory of Professor Norman Bowery (1944–2016). Norman was a unique, intuitive pharmacologist who spent most of his career researching the pharmacology of γ-aminobutyric acid (GABA). He discovered a novel metabotropic receptor sub-type, GABA_B, that is pharmacologically and structurally different from the original ionotropic receptor designated GABA_A. In his research he also studied the neurotransmitters glutamate and substance P, two molecules whose release in parts of the spinal cord is inhibited by baclofen, a GABA_B receptor agonist. Norman was interested in the therapeutic potential of interacting with the GABA_B receptor, in particular spasticity, pain and absence epilepsy.

 Professor Norman G Bowery  in July 2010 at Tregnago (VR), Italy.
 

Norman gained his PhD in pharmacology from the University of London in 1974. In 1987 he received his DSc, also from the University of London. The University of Florence, Italy, recognised his work in 1992 when he was awarded the degree of Laurea Honoris Causa. In 2004, Norman’s career was recognised again, this time by the British Pharmacological Society when he was elected an Honorary Fellow (HonFBPhS). For his research on the Pharmacology of GABA_B receptors, he was awarded the prestigious Gaddum Memorial Gold Medal Award in 2008, the highest honour the Society awards for outstanding contributions to Pharmacology.

During his career, Norman was a great advocate of pharmacology. He was a member of the Editorial Board of a number of journals, including: the British Journal of Pharmacology; Neuropharmacology; Epilepsy Research; the Journal of Pharmacy and Pharmacology; the Journal of Pharmacological and Toxicological Methods; Brain; and Trends in Pharmacological Sciences. In addition to Current Opinions in Pharmacology (COPHAR), Norman was Editor-in-Chief of Pharmacology Reviews and Communications, and the Journal of Neuroscience Methods. For a time, he was a member of the International Union of Pharmacology (IUPHAR)’s Nomenclature Committee, as well as both Meeting Secretary and President of the British Pharmacological Society.

Norman’s career spanned both academia and industry. He became a postgraduate at the School of Pharmacy in London in 1973, where he then progressed to a teaching fellow.  Later he worked as a lecturer and then senior lecturer at St. Thomas’s Hospital Medical School, also in London. During this period, Norman was working and publishing on GABA in ganglia and neuronal and glial cells amongst others, laying the foundation for his work on the GABA_B receptor.

Norman will almost certainly be best remembered for his work on this GABA_B receptor. In the book GABA_B Receptor Pharmacology: A Tribute to Norman Bowery, published in 2010 to mark the 30^th anniversary of the discovery of the GABA_B receptor, the following was written in the preface by Enna and Blackburn, ‘it is noteworthy that the discovery and initial characterization of this (receptor) site can so easily be traced to a single person, Norman Bowery.’

In a tribute published in Neuropharmacology in 2018, Bettler, Crunelli and Enna’s editorial affectionately expressed how the ‘B’ in GABA_B would always stand for ‘Bowery’ in their minds.

In 1984, Norman took up his first spell working in the pharmaceutical industry at Merck Sharp and Dohme Research Laboratories, Harlow, UK. Norman returned to academia three years later, being appointed as Professor of Pharmacology at the School of Pharmacy, London. Here, Norman continued his work on GABA, glycine and other transmitters such as serotonin, glutamate and substance P. In addition to classical pharmacological work on these neurotransmitters, Norman researched and published work on receptor distribution in in vitro brain slices of mouse, rat, monkey and human, including from patients. Norman moved from London to Birmingham in 1995 to be a Professor of Pharmacology at the University of Birmingham Medical School, where he continued studies on GABA, glycine and glutamate function and receptor distribution. He also mentored a young Nick Barnes, who years later became Professor of Pharmacology at Birmingham.

In 2004, Norman returned for a second time to industry as Head of Biology in the Psychiatry Centre of Excellence for Drug Discovery (Psychiatry CEDD) at GSK Verona, Italy. In the same year, he was appointed Professor Emeritus at the University of Birmingham. Norman retired from GSK in 2006 but continued to publish articles and book chapters.

During his career, Norman has raised three generations of young scientists through mentoring and supervising graduate and doctoral pharmacologists.

Norman Bowery’s pioneering contribution to pharmacology and drug development has to reference the discovery of the GABA_B receptor in the context of the time of its classification. The term GABA_B was coined in 1981. The process of arriving at this novel receptor for GABA was steeped in traditional pharmacological methodology. The starting point was that the he first found that the effect of GABA was not confined to neurons of the central nervous system (CNS), but was also evident in neurons in the periphery. In these neurons the application of GABA produced a smaller reversal potential than in the CNS, causing an outward flux of anions leading to depolarisation instead of hyperpolarisation. At this point, Norman used an indirect approach to measure depolarisation in sympathetic terminals, studying the effect of GABA on the release of radiolabelled noradrenaline in preloaded isolated atrium.

At this time, receptor classification relied on the use of selective antagonists and agonists. These defined the receptor, and subsequent novel ligand-receptor interactions classified the ligand, be it antagonist or agonist. In the case of GABA_B, classification involved the use of a selective agonist and a selective antagonist in functional and radioactive binding studies, receptor distribution and differential transduction. In fact, GABA_B receptor classification was undertaken just a few years before receptor structural information started to become available as a tool in classification (e.g. the Beta adrenergic receptor)). In fact, it was 10 years before the structure of the classical ionotropic GABA_A receptor was identified.

In the case of GABA_B, its classification relied upon the elucidation of a selective agonist baclofen, and the lack of effect of a selective antagonist bicuculline. The former, a derivative of GABA (β p-chlorophenyl GABA), was inactive on the traditional GABA receptor found in the CNS that causes increases in neuronal membrane permeability to Cl^- causing a hyperpolarisation, whereas, it mimicked the effect of GABA in peripheral sympathetic and dorsal root ganglia neurons. In fact, with this work Norman also demonstrated the mode of action of baclofen, a molecule that had been in the clinic since the 1970’s, to treat spasticity. Importantly, the competitive GABA antagonist bicuculline was inactive against baclofen on this peripheral sympathetic GABA response, reinforcing the idea of a novel GABA receptor. Later, when selective GABA_B receptor antagonists became available, their application provided further evidence for sub-types of GABA receptors. Finally, it was shown that unlike the central GABA receptor that once activated allows an increase in Cl^- conductance (an ionotropic receptor) the novel receptor site was metabotropic. Some ten years after the traditional GABA_A receptor structure was published, the GABA_B receptor was shown to be a heterodimer consisting of a GABA binding B1 7-TM subunit together with a second B2 7-TM subunit that interacts with a G-protein. The latter also contains an allosteric binding site. Agonist induced activation is translated through the G-protein, in this case to indirectly act on K⁺ and Ca²⁺ channels.

Therapeutic implications of GABA_B

Norman was always passionate about the potential therapeutic benefits of agents acting at the GABA_B receptor and this led him also to a wider consideration of the neurotransmitters that GABA_B receptor activation might modify. The existing clinical use of baclofen in spasticity of spinal and cerebral causes meant that these diseases were a prime target for selective GABA_B agonists from the moment of his discovery of this novel receptor. Baclofen has been used as a muscle relaxant and this action can be blocked by the GABA_B receptor antagonist CGP35348, supporting an involvement of the GABA_B receptor.

Baclofen has numerous side-effects that makes it unsuitable as high doses need to be given to get adequate brain penetration. Intrathecal administration via an indwelling pump has essentially surmounted the side-effect problem. However, an orally acting molecule would be an advantage.

GABA_B receptors can be both pre-synaptic and post-synaptic. In the ventral horn of the spinal cord the action of baclofen is to depress neurotransmitter release through agonist activity at the pre-synaptic receptor. Baclofen inhibits glutamatergic post-synaptic currents and prevents the internalisation of Neurokinin-1 (NK₁) receptors caused by noxious stimulation. This might be considered a surrogate for substance P release. Substance P causes a rapid internalization of NK₁ receptors. The effect of baclofen on glutamate and substance P reinforced the hypothesis that GABA_B receptors, due to their spinal localisation and baclofen’s antinociceptive effect in animal models, may have utility in pain. In humans, baclofen shows an antinociceptive effect, but with rapid tolerance, whereas intrathecal administration of baclofen reduces central pain with little tolerance.

Whether through his interest in GABA or for other reasons during his career, Norman had collaborations and publications around the NMDA receptor. The data is not very conclusive on the role of NK₁ receptors in pain. Interestingly however, based on the observation that Substance P causes rapid internalisation of NK₁ receptors, a Substance P-Saporin (SP-SAP) conjugate is under evaluation in cancer pain. SAP is a ribosome-inactivating protein that when delivered and internalised via NK₁ receptors on laminae I and X of the dorsal horn ablates these NK₁ receptors in neurons, delivering relief in animal models of pain. Thus, whilst blocking NK₁ receptors does not show activity against pain states in the clinic, substance P receptors might offer an innovative way to selectively deliver a toxin to inactivate neurons known to be involved in severe cancer pain.

Norman maintained an interest in substance P and the NK₁ receptor in the spinal cord, as he did with a number of other neurotransmitters acting in the CNS and their receptors. These included: glycine, serotonin (5HT_3, 5-HT1_A), β-adrenoceptors and Calcitonin gene-related peptide (CGRP).

In his 2006 COPHAR article Norman showed that he was not only interested in the pharmacology of the novel GABA_B receptor that he first described, but was very curious in the potential therapeutic application of specific agonists and antagonists. In particular, diseases such as spasticity, pain, cognition, drug addiction, depression, anxiety and epilepsy were all highlighted in his article.

As a pioneering pharmacologist, Professor and departmental head, he built up many collaborations and alliances across the world, from which arose a multitude of friendships. The British Pharmacological Society is pleased to honour Norman Bowery’s pioneering contributions to pharmacology and drug discovery at Pharmacology 2019.

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