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Povl Krogsgaard-Larsen

GABA

Povl Krogsgaard-Larsen is a professor of medicinal chemistry at The Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen. As Associate Professor, he established a research program focusing on conversion of naturally occurring toxins into specific pharmacological tools and therapeutic agents. Key lead structures in this research program were secondary metabolites of Amanita muscaria, muscimol and ibotenic acid, as well as constituents of the Areca nut alkaloid, arecoline, all of which interact non-selectively with GABA, glutamate, and muscarinic receptors, respectively. As well as being an accomplished scientist Povl Krogsgaard-Larsen became a well regarded businessman later in life and contributed to various philanthropic efforts within Denmark.

Early Life

Povl Krogsgaard-Larsen was born May 17, 1941 in Mollerup on the island of Mors. Born to Niels Saaby-Larsen and Marie Sofie-Krogsgaard on a small farm. He grew up with his older sister Birthe and two younger brothers Knud and Jørgen. Povl Krogsgaard-Larsen as a small child was a trouble maker, explorer, and later a "pattern breaker". Growing up on a small farm in Mollerup and then later moving to a larger farm in Sundby on his 10th birthday. Povl Krogsgaard-Larsen was often times more interested in exploring his surroundings and being creative than following in the footsteps of his father and grandfather as farmers. Being quite skilled in the art of wood carving he was encouraged by his parents to become a carpenter, though for some time he made a hobby out of digging up fossils and artifacts in Sundby thinking that he could carve out a path for himself as an archeologist. It was not until his chemistry teacher at Nykøbing high school encouraged him to study chemistry and pharmacology due to his fascination with understadning biological toxins that he decided he would become a pharmacist and chemist. However his hopes and dreams of studying chemistry in Copenhagen were postponed when he was conscripted due to the ongoing cold war. Despite being a proficient soldier and being recommended for multiple promotions Povl knew his future was in academics at the University of Copenhagen. First becoming a disciple at a pharmacy in Nykøbing before later being accepted in the School of Pharmaceutical Sciences at the University of Copenhagen in 1964 with his wife Tove who he would later marry he set out on becoming a researcher.

Career

muscimol

ibotenic acid

Gaboxadol

Synthesis of Gaboxadol

After Graduating from the University of Copenhagen in 1967 Povl was offered a lecturer's position at the College of Pharmacy by professor Bodil Jerslev and boldly given the task start a new medicinal chemistry program. Jerslev herself studied crystallography of oximes and had impressed upon Povl the importance of the "N-O bond" in future pharmaceuticals. Fortunately for Povl an article published in the journal "Fortschritte der Chemie organischer Naturstoffe" came across his desk soon after he accepted the job offer. The publication pertained to the red fly agaric mushroom or Amanita muscaria that possesses peculiar isoxazole natural products. Growing up in the country side of Mors Povl was no stranger to these mushrooms that had fascinated him and many others as a child. Known to have been used by Siberian tribes as a hallucinogen and by viking berserkers. Povl famously decided this would be the start of his new research program. "By the time I finished reading the article, my fate was sealed. I had only one thought: Here is your research project." Indeed the natural products within this mushroom became the foundation for Povl's academic career for the next 40 years. The first major breakthrough for Povl came in 1974 as a visiting professor at the University of Canberra in Australia while doing in vitro tests on eleven analogs of the natural products found within Amanita muscaria. These tests ultimately revealed that nipecotic acid and derivatives thereof could inhibit GABA transport which at the time was a major discovery that lead to a publication in the Journal of Neurochemistry in 1975 with Dr. Graham A. R. Johnston. This discovery resulted in numerous subsequent publications concerning novel analogs of the natural products contained within the Areca nut and Amanita muscaria and there activity on GABA receptors. Perhaps most famously Gaboxadol was synthesized and studied that same year along with other GABA uptake inhibitors and agonists. Gaboxadol however had unique potential not only because of its potency but importantly its reduced toxicity. As was somewhat common at the time Povl carried out a series of self experiments with this new drug to better understand the effects qualitatively. The drug was then patented and licensed to Lundbeck where it underwent a series of human tests to evaluate its potential for the treatment of various neurological disorders, Huntington's disease, and cancer. Gaboxadol, however promising, failed every trial it was placed in due to side effects of delirium, hallucination, and sedation. It wasn't until 1996 that researchers at the Max Planck Institute for Psychiatry in Munich attempted to utilize Gaboxadol's frequently reported sedative side effects as a treatment for insomnia. These studies lead to Merck paying Lundbeck $270 million for the rights to sell Gaboxadol in the United States for use as a hypnotic. Gaboxadol never made it to market however when it failed a phase 3 clinical trial after an amphetamine addict reported having hallucinations at high doses in 2007. As of 2015, Ovid Therapeutics owns the rights to Gaboxadol and plans to develop it for treatment of FXS and Angelman syndrome. Despite these failures with Gaboxadol Krogsgaard-Larsen was able to make a number of important scientific discoveries along the way including the unveiling of the AMPA receptor subgroup as well as the muscarinic receptor subgroup both of which were elucidated through the synthesis of a range of subtype-selective glutamate receptor agonists and antagonists. Importantly nipecotic acid was later developed into the antiepileptic drug Tiagabine.

Business

Povl Krogsgaard-Larsen has served as a chairman for various companies based in Denmark notably he was chairman of the Carlsberg Foundation and of Carlsberg A/S until 2012. Until 2016 he was also a member of the board for The Lundbeck Foundation, one of the largest private contributors to research and education in Denmark with a focus on neuroscience, biomedical research, and social issues.

Books

• Specific GABA receptor agonists and uptake inhibitors: Design, development, and structure-activity studies. FADL'S Forlag (1980). ISBN 9788774377832.
• Glutamate and GABA Receptors and Transporters: Structure, Function and Pharmacology, with Jan Egebjerg and Arne Schousboe. CRC Press (2001). ISBN 9780748408818.
• Textbook of Drug Design and Discovery, with Ulf Madsen and Tommy Lijefors. CRC Press (2002). ISBN 9780415282888.
• Advanced Computer-Assisted Techniques in Drug Discovery, with Han van de Waterbeemd, Raimund Mannhold, and Hendrik Timmerman. John Wiley & Sons (2008). ISBN 9783527615667.
• Chemometric Methods in Molecular Design, with Han van de Waterbeemd, Raimund Mannhold, and Hendrik Timmerman. John Wiley & Sons (2008). ISBN 9783527615445.

Achievements

Povl Krogsgaard-Larsen acquired his DSc degree, and has published over 440 scientific papers. He has edited a number of books, and was the European Editor for the Journal of Medicinal Chemistry from 1998-2013. He has been awarded honorary doctor degrees at Strasbourg (1992), Uppsala (2000), and Milan (2008) Universities. He has received numerous scientific awards and prizes, and he is member of The Royal Danish Academy of Sciences and Letters.