Leslie Iversen

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Leslie Lars Iversen (born October 31, 1937 in Exeter , † July 30, 2020 ) was a British pharmacologist . He gained important knowledge about the transport of neurotransmitters such as the catecholamines noradrenaline , adrenaline and dopamine and the amino acids γ-aminobutyric acid (GABA) and glycine from the extracellular space into cells. The cellular uptake is accompanied by a loss of effectiveness, because these neurotransmitters reach their effect-mediating receptors from the extracellular space.

Life

Iversen's parents immigrated to England from Denmark in the 1920s, where his father became manager of a division of the Danish Bacon Company , now part of the Danish Crown group of companies . Leslie attended Hele's School in Exeter, corresponding to a German high school . After two years in the Royal Navy , he studied botany, chemistry and physiology as a member of Trinity College , Cambridge , before focusing on biochemistry . In 1961, at the end of his undergraduate studies , he married his fellow student Susan Kibble, who in 1993 became Susan D. Iversen professor of experimental psychology at Oxford . The work on his dissertation was supervised by Lionel Gordon Whitby (1926-2000), who had just returned to Cambridge from working with Julius Axelrod at the National Institutes of Health in Bethesda , and then by Arnold Burgen , the newly appointed professor of pharmacology in Cambridge. In 1964 Iversen received a Ph.D. PhD . As almost indispensable for natural scientists, he then worked in US laboratories, through the mediation of Gordon Whitby, at Axelrod in Bethesda, then with Stephen Kuffler at the Department of Neurobiology at Harvard Medical School in Boston . In 1966 he returned to the Cambridge Pharmacological Institute. Thanks to a research grant, he had no teaching commitments other than evening tutorials at Trinity College. From 1970 to 1983 he headed a newly established Neurochemical Pharmacology Research Group of the Medical Research Council in Cambridge . In 1983 he took a step, the sometimes frowned upon by his academic colleagues, was part admired: He became director of the newly established Neuroscience Research Center - Neuroscience Research Center of Merck, Sharp & Dohme in Hoddesdon , Hertfordshire , which in the coming years up to 300 Salaried employees, but was closed in 2004 as part of the company's austerity measures after the market withdrawal of its drug Vioxx ® with the active ingredient rofecoxib . Iversen left Merck, Sharp & Dohme in 1995, became a visiting professor at the Oxford Pharmacological Institute and at the same time founded his own startup company Panos Therapeutics Ltd. In which a license from Merck, Sharp & Dohme cholecystokinin - antagonists have been developed. There were also other university and consultant positions.

research

Catecholamines

The description of the psychological effects of mescaline in Aldous Huxley's essay The Doors of Perception made Iversen curious about the mode of action of psychotropic substances . This curiosity found a concrete goal through Gordon Whitby. In Bethesda, Whitby, together with Axelrod and Georg Hertting, discovered a new way in which the neurotransmitter noradrenaline was removed from the extracellular space after its release from the presynaptic axon endings of sympathetic neurons : namely by being taken back into the axon endings by means of membrane transport. The discovery was made using radiolabeled , ie 3 H noradrenaline. It seemed particularly interesting that the resumption was inhibited by some psychotropic substances such as cocaine . The same discovery was made independently by the German pharmacologist Erich Muscholl in Mainz.

Whitby and Iversen first carried out similar experiments on anesthetized mice in Cambridge. Assuming that the membrane transport should obey the Michaelis-Menten theory , Iversen then investigated its kinetics in detail in isolated hearts from rats. The assumption was confirmed. Cocaine competitively inhibited uptake . However, something surprising emerged. At very high concentrations of noradrenaline - or also adrenaline - the previously characterized transport was joined by a second transport with different Michaelis-Menten kinetics and different sensitivity to inhibitors. Ivensen called it Uptake 2 to distinguish it from the longer known Uptake 1 . Today (2013) both transporters are known down to their genes and protein structure; Uptake 1 is mediated by the noradrenaline transporter (NAT or NET), uptake 2 by the "extraneuronal monoamine transporter" EMT. Both belong to the group of SLC transporters (SLC for s o l ute c arrier).

In Axelrod's laboratory in Bethesda, Iversen met Jacques Glowinski (* 1936), a French pharmacologist of the same age. It was now known that there were also nerve cells in the central nervous system with noradrenaline, adrenaline and the third endogenous catecholamine, dopamine. Iversen and Glowinski injected the 3 H-catecholamines into the cerebral ventricles and described in a series of four publications their distribution and metabolism in different areas of the brain as well as the effect of psychotropic drugs on distribution and metabolism. The first of the four publications was Iversen's most successful bibliometrically . In 1967 Iversen summarized the state of knowledge in his book "The Uptake and Storage of Noradrenaline in Sympathetic Nerves". In addition to the title, the book deals with dopamine and adrenaline as well as the catecholamines in the central nervous system.

The catecholamines continued to accompany Iversen. In Boston his group found that uptake 1 required the presence of Na + ions in the extracellular space, back in Cambridge that uptake 2 was inhibited by steroids such as estradiol and corticosterone . Thanks mainly to Hans Thoenen , it was known that 6-hydroxydopamine was a poison for peripheral sympathetic nerve cells. The Neurochemical Pharmacology in Cambridge showed that it noradrenaline and dopamine neurons destroyed in the brain. It then served to clarify the function of these neurons. Together with Thoenen, the group demonstrated that nerve growth factor was transported retrograde from the presynaptic endings of sympathetic nerves into the cell body . The group showed that contrary to the classical idea, the dopaminergic neurons of the substantia nigra released their transmitter not only from the presynaptic endings, but also from the dendrites .

Finally, catecholamine research includes contributions to pathogenesis . Together with the US neuroanatomist Floyd Bloom (* 1936), the Cambridge group confirmed that Alzheimer's disease resulted in a loss not only of acetylcholine neurons but also of noradrenaline neurons in the brain.

Around 1970, the dopamine hypothesis was the focus of research on the pathogenesis of schizophrenia : an overactivity of dopaminergic neurons in the brain contributed to its symptoms. An important support was the observation that the neuroleptics used therapeutically blocked dopamine receptors. Iversen's group used a biochemical effect of dopamine for their experiments, the stimulation of the enzyme adenylyl cyclase and thus the formation of the second messenger cyclo-AMP . In fact, some neuroleptics such as chlorpromazine and fluphenazine strongly weakened this biochemical effect of dopamine, while others such as the butyrophenone spiroperidol only weakly, weaker than expected based on their clinical effectiveness. Even in a somewhat later review article by Iversen, the contradiction remained unsolved. It only found its explanation with the discovery of several types of dopamine receptors, of which not D 1 and D 5 , which stimulate adenylyl cyclase, mediate the therapeutic effect, but D 2 and D 4 , which inhibit adenylyl cyclase (and trigger other secondary reactions) .

With this work with, Iversen inscribed himself in the history of catecholamine research . In comparison, his research on other subjects has remained less extensive.

Amino acid transmitter

Stephen Kufler at Harvard Medical School did research on γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. It occurs, among other things, in the nerves of lobsters that inhibit the animals' muscles. Iversen and his co-workers showed in 1966 that these nerves released GABA into the extracellular space upon electrical stimulation; The authors call it an experimentum crucis . It was Iversen's first study of an amino acid transmitter. As with the catecholamines, the question of elimination from the extracellular space arose. It was again - found in 1968 in Cambridge on sections of the cerebral cortex of rats - uptake in cells, obeying Michaelis-Menten kinetics and dependent on the presence of Na + in the extracellular space. The receiving cells were predominantly the presynaptic endings of the GABA neurons, so that after the previous release, the uptake was a resumption. However, glial cells also took up GABA.

The second inhibitory amino acid transmitter, glycine, was also taken up in cells, especially in the presynaptic endings of glycine neurons.

In 1990 the gene of a GABA transporter was cloned . This GABA transporter (there are several) thus became the prototype of the subfamily of SLC transporters, which use the Na + concentration gradient from the extra to the intracellular space and are known as sodium neurotransmitter symporters . The noradrenaline transporter and the glycine transporter (there are also several) belong to this SLC subfamily, "SLC6".

A few years before Iversen took over the Neuroscience Research Center in Hoddesdon, scientists from Merck, Sharp & Dohme in the US had discovered a new anticonvulsant , MK-801 or dizocilpine. In 1988 Iversen clarified the mechanism: The substance was a non-competitive antagonist at the NMDA receptor , one of several receptors for glutamate , the most important excitatory amino acid transmitter in the central nervous system. Dizocilpine was not introduced as a drug because of undesirable side effects; however, Iversen researched further. Dizocilpine bound to the same site in the NMDA receptor as ketamine and phencyclidine , which is abused as a psychotropic substance. Two newer designer drugs, a ketamine and a phencyclidine derivative, worked by the same mechanism.

Regardless of its effect as an independent inhibitory neurotransmitter, glycine intensifies the excitatory effect of glutamate via a special glycine binding site on the NMDA receptor. Iversen's group identified substances that blocked the binding site and thereby counteracted the glutamate, in particular protected against excitotoxicity . Shortly before he left Merck, Iversen concluded (from English): “According to preclinical studies, antagonists at the glycine binding site have great therapeutic potential. For the clinic, however, substances must first be found that can cross the blood-brain barrier . "

Neuropeptides

Iversen's interest turned to peptide neurotransmitters when Hans Kosterlitz , John Hughes and their group discovered the endogenous opioids leucine-enkephalin and methionine-enkephalin in 1975 . Iversen began to measure the release of peptides from sections of brain areas: the enkephalins from the globus pallidus , the tachykinin substance P , somatostatin and neurotensin from the hypothalamus . As expected for neurotransmitters, high K + concentrations released the peptides, but only in the presence of Ca 2+ ions . There was no resumption in the presynaptic endings as with the catecholamines and amino acids.

The history of research into neuropeptides began much earlier, in 1953, with the assumption of the Austrian pharmacologist Fred Lembeck in Graz that substance P could be a transmitter for the primary neuron of the pain pathway . Iversen and his doctoral student Thomas Jessell found indirect evidence for this: High K + concentrations also released substance P from the presynaptic endings of the trigeminal nerve in the brainstem, which mediates pain perception, while pain reliever opioids such as morphine inhibited the release, and the opioid antagonist naloxone again removed opioid inhibition. Jessell and Iversen put Lembeck's essay first in their list of citations. Shortly before, the group of the pharmacologist Klaus Starke in Essen had found the inhibition of the release of another central nervous system transmitter, noradrenaline, via opioid receptors. But Jessell and Iversen brought the anatomy of the pain pathway, the suspected pain transmitter substance P and the analgesic effect of the opioids into a plausible context for the first time. A treatment lasting several days with the paprika substance capsaicin makes test animals insensitive to some pain stimuli. In agreement with Lembeck's hypothesis, Iversen's group found that substance P had disappeared from the primary neurons of the pain pathway. When the existence of several types of opioid receptors became apparent, Iversen's group detected both the μ and δ types on substance P neurons.

Substance P research at Cambridge's Neurochemical Pharmacology provided evidence of the existence of several types of substance P receptors , tachykinin receptors . At the Neuroscience Research Center , the search for tachykinin antagonists became a major project. Not in Iversen's time, but later on the antiemetic aprepitant emerged, a selective antagonist of tachykinin NK 1 receptors, which was marketed as Emend ® .

recognition

In 1971 the British Pharmacological Society commissioned Iversen with the third lecture in memory of the British pharmacologist John Gaddum . In 1980 he became a member of the Royal Society , 1981 of the American Academy of Arts and Sciences , 1986 of the National Academy of Sciences of the USA. In 2003 he received the Wellcome Gold Medal from the British Pharmacological Society . From 1989 he was a member of the Academia Europaea .

literature

Individual evidence

  1. ↑ Obituary
  2. ↑ John Cash: Lionel Gordon Whitby . Retrieved November 29, 2013.
  3. ↑ G. Hertting, J. Axelrod: Fate of tritiated noradrenaline at the sympathetic nerve endings . In: Nature . 192, 1961, pp. 172-173. doi : 10.1038 / 192172a0 . PMID 13906919 .
  4. ↑ Julius Axelrod, LG Whitby, Georg Hertting: Effect of psychotropic drugs on the uptake of H 3 -norepinephrine by tissues . In: Science . 133, 1961, pp. 383-384. doi : 10.1126 / science.133.3450.383 . PMID 13685337 .
  5. ↑ LL Iversen, LG Whitby: Retention of injected catecholamines by the mouse . In: British Journal of Pharmacology . 19, 1962, pp. 355-364. doi : 10.1111 / j.1476-5381.1962.tb01199.x .
  6. ↑ LL Iversen: The uptake of noradrenaline by the isolated perfused rat heart . In: British Journal of Pharmacology . 21, 1963, pp. 523-537. doi : 10.1111 / j.1476-5381.1963.tb02020.x .
  7. ↑ LL Iversen: The uptake of catecholamines at high perfusion concentrations in the rat isolated heart: a novel catecholamine uptake process . In: British Journal of Pharmacology . 1965, pp. -. doi : 10.1111 / j.1476-5381.1965.tb01753.x .
  8. ↑ a b Jacques Glowinski, Leslie L. Iversen: Regional studies of catecholamines in the brain - I. The disposition of [ 3 H] norepinephrine, [ 3 H] dopamine and [ 3 H] DOPA in various regions of the brain . In: Journal of Neurochemistry . 13, 1966, pp. 655-669. doi : 10.1111 / j.1471-4159.1966.tb09873.x .
  9. ^ Jacques Glowinski, Julius Axelrod, Leslie L. Iversen: Regional studies of catecholamines in the rat brain. IV. Effects of drugs on the disposition and metabolism of H 3 -norepinephrine and H 3 -dopamine. . In: Journal of Pharmacology and Experimental Therapeutics . 153, 1966, pp. 30-41. PMID 4380692 .
  10. ^ Leslie L. Iversen: The Uptake and Storage of Noradrenaline in Sympathetic Nerves. Cambridge University Press , Cambridge 1967.
  11. ↑ LL Iversen, EA Kravitz: Sodium dependence of transmitter uptake at adrenergic nerve terminals . In: Molecular Pharmacology . 2, No. 4, 1966, pp. 360-362. PMID 5968076 .
  12. ↑ LL Iversen, PJ Salt: Inhibition of catecholamine uptake 2 by steroids in the isolated rat heart . In: British Journal of Pharmacology . 40, 1970, pp. 528-530. doi : 10.1111 / j.1476-5381.1970.tb10637.x . PMID 5497802 .
  13. ↑ NJ Uretzky, LL Iversen: Effects of 6-hydroxydopamine on catecholamine containing neurones in the rat brain . In: Journal of Neurochemistry . 17, No. 2, 1970, pp. 269-278. doi : 10.1111 / j.1471-4159.1970.tb02210.x . PMID 5494056 .
  14. ^ IA Hendry, K. Stöckel, H. Thoenen, LL Iversen: The retrograde axonal transport of nerve growth factor . In: Brain Research . 68, No. 1, 1974, pp. 103-121. doi : 10.1016 / 0006-8993 (74) 90536-8 . PMID 4143411 .
  15. ↑ LB Geffen, JM Jessell, AC Cuello, LL Iversen: Release of dopamine from dendrites in rat substantia nigra . In: Nature . 260, 1976, pp. 258-260. doi : 10.1038 / 260258a0 . PMID 1256567 .
  16. ↑ LL Iversen, MN Rossor, GP Reynolds, R. Hills, M. Roth, CQ Mountjoy, SL Foote, JH Morrison, FE Bloom: Loss of pigmented dopamine-β-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type . In: Neuroscience Letters . 39, No. 1, 1983, pp. 95-100. doi : 10.1016 / 0304-3940 (83) 90171-4 . PMID 6633940 .
  17. ↑ Richard J. Miller, Alans S. Horn, Leslie L. Iversen: The action of neuroleptic drugs on dopamine-stimulated adenosine cyclic 3 ', 5'-monophosphate production in rat neostriatum and limbic forebrain. . In: Molecular Pharmacology . 10, 1974, pp. 759-766.
  18. ^ Leslie L. Iversen: Dopamine receptors in the brain . In: Science . 188, 1975, pp. 1084-1089. doi : 10.1126 / science.2976 .
  19. ↑ H. Bönisch, E. Schlicker, M. Göthert, W. Maier: Psychopharmaka - Pharmacotherapy of mental illnesses. In: In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke (eds.): General and special pharmacology and toxicology. 11th edition, Munich, Elsevier GmbH 2013, pages 307–341. ISBN 978-3-437-42523-3
  20. ↑ M. Otsuka, LL Iversen, ZW Hall, EA Kravitz: Release of gamma-aminobutyric acid from inhibitory nerves of lobster . In: Proceedings of the National Academy of Sciences . 56, No. 4, 1966, pp. 1110-1115. doi : 10.1073 / pnas.56.4.1110 . PMID 5230136 .
  21. ↑ LL Iversen, MJ Neal: The uptake of 3 [H] GABA by slices of rat cerebral cortex . In: Journal of Neurochemistry . 15, 1968, pp. 1141-1149. doi : 10.1111 / j.1471-4159.1968.tb06831.x . PMID 5711127 .
  22. ↑ FE Bloom, LL Iversen: Localizing 3 H-GABA in nerve terminals of rat cerebral cortex by electron microscopic autoradiography . In: Nature . 229, 1971, pp. 628-630. doi : 10.1038 / 229628a0 .
  23. ↑ a b L. L. Iversen, FE Bloom: Studies of the uptake of 3 H-GABA and [ 3 H] glycine in slices and homogenates of rat brain and spinal cord by electron microscopic autoradiography . In: Brain Research . 41, 1972, pp. 131-143. doi : 10.1016 / 0006-8993 (72) 90621-X . PMID 5036031 .
  24. ↑ MJ Neal, LL Iversen: Autoradiographic localization of 3 H-GABA in rat retina . In: Nature . 235, 1972, pp. 217-218. doi : 10.1038 / newbio235217a0 . PMID 4334931 .
  25. ↑ LL Iversen, JS Kelly: Uptake and metabolism of γ-aminobutyric acid by neurones and glial cells . In: Biochemical Pharmacology . 24, No. 9, 1975, pp. 933-938. doi : 10.1016 / 0006-2952 (75) 90422-0 . PMID 1156449 .
  26. ↑ GAR Johnston, LL Iversen: Glycin uptake in rat central nervous system slices and homogenates: evidence for different uptake systems in spinal cord and cerebral cortex . In: Journal of Neurochemistry . 18, 1971, pp. 1951-1961. doi : 10.1111 / j.1471-4159.1971.tb09601.x .
  27. ↑ J. Guastella, N. Nelson, H. Nelson, L. Czyzyk, S. Keynan, MC Miedel, N. Davidson, HA Lester, BI Kanner: Cloning and expression of a rat brain GABA transporter . In: Science . 249, 1990, pp. 1303-1306. doi : 10.1126 / science.1975955 .
  28. ↑ Nian-Hang Chen, Maarten EA Reith, Michael W. Quick: Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6 . In: Pflügers Archive - European Journal of Physiology . 447, 2004, pp. 519-531. doi : 10.1007 / s00424-003-1064-5 .
  29. ↑ EH Wong, JA Kemp, T. Priestley, AR Knight, GN Woodruff, LL Iversen: The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist . In: Proceedings of the National Academy of Sciences . 83, 1986, pp. 7104-7108. doi : 10.1073 / pnas.83.18.7104 . PMID 3529096 .
  30. ↑ Bryan L. Roth, Simon Gibbons, Warunya Arunotayanun, Xi-Ping Huang, Vincent Setola, Ric Treble, Les Iversen: The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor . In: PLOS ONE . 8, No. 3, 2013, pp. 1-5. doi : 10.1371 / journal.pone.0059334 .
  31. ↑ JA Kemp, AC Foster, PD Leeson, T. Priestley, R. Tridgett, LL Iversen, GN Woodruff: 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex . In: Proceedings of the National Academy of Sciences . 85, 1988, pp. 6547-6550. doi : 10.1073 / pnas.85.17.6547 . PMID 2842779 .
  32. ↑ L. Singh, AE Donald, AC Foster, PH Hutson, LL Iversen, SD Iversen, JA Kemp, PD Leeson, GR Marshall, RJ Oles: Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+) - HA-966 is a selective glycine / N-methyl-D-aspartate receptor antagonist, but (-) - HA-966 is a potent gamma-butyrolactone-like sedative . In: Proceedings of the National Academy of Sciences . 87, 1990, pp. 347-351. doi : 10.1073 / pnas.87.1.347 . PMID 2153294 .
  33. ^ Paul D. Leeson, Leslie L. Iversen: The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential . In: Journal of Medicinal Chemistry . 37, No. 24, 1994, pp. 4053-4067. doi : 10.1021 / jm00050a001 .
  34. ↑ LL Iversen, SD Iversen, FE Bloom, T. Vargo, R. Guillemin: Release of enkephalin from rat globus pallidus in vitro . In: Nature . 271, 1978, pp. 679-681. doi : 10.1038 / 271679a0 . PMID 24182 .
  35. ↑ LL Iversen, T. Jessell, I. Kanazawa: Release and metabolism of substance P in rat hypothalamus . In: Nature . 264, 1976, pp. 81-83. doi : 10.1038 / 264081a0 .
  36. ↑ LL Iversen, SD Iversen, F. Bloom, C. Douglas, M. Brown, W. Vale: Calcium-dependent release of somatostatin and neurotensin from rat brain in vitro . In: Nature . 273, 1978, pp. 161-163. doi : 10.1038 / 273161a0 . PMID 643079 .
  37. ↑ F. Lembeck: On the question of the central transmission of afferent impulses. III. Message. The occurrence and importance of substance P in the dorsal roots of the spinal cord . In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology . 219, 1953, pp. 197-213. doi : 10.1007 / BF00246293 .
  38. ↑ TM Jessell, LL Iversen: Opiate analgesics inhibit substance P release from rat trigeminal nucleus . In: Nature . 268, 1977, pp. 549-551. doi : 10.1038 / 268549a0 . PMID 18681 .
  39. ^ H. Montel, K. Starke and F. Weber: Influence of morphine and naloxone on the release of noradrenaline from rat brain cortex slices. In: Naunyn-Schmiedeberg's Archives of Pharmacology 1974; 283: 357-369. PMID 4154063 . doi : 10.1007 / BF00501287
  40. ↑ TM Jessell, LL Iversen, AC Cuello: Capsaicin-induced depletion of substance P from primary sensory neurones . In: Brain Research . 152, No. 1, 1978, pp. 183-188. doi : 10.1016 / 0006-8993 (78) 90146-4 . PMID 209869 .
  41. ↑ HL Fields, PC Emson, BK Leigh, RFT Gilbert, LL Iversen: Multiple opiate receptor sites on primary afferent fibers . In: Nature . 284, 1980, pp. 351-353. doi : 10.1038 / 284351a0 . PMID 6244504 .
  42. ↑ Chi-Ming Lee, Leslie L. Iversen, Michael R. Hanley, Bengt EB Sandberg: The possible existence of multiple receptors for substance P . In: Naunyn-Schmiedeberg's Archives of Pharmacology . 318, No. 4, 1982, pp. 281-287. doi : 10.1007 / BF00501166 . PMID 6176885 .
  43. ↑ LL Iversen: Role of transmitter uptake mechanisms in synaptic neurotransmission. Third Gaddum Memorial Lecture: Royal College of Surgeons, September 1970 . In: British Journal of Pharmacology . 41, 1971, pp. 571-591. doi : 10.1111 / j.1476-5381.1971.tb07066.x . PMID 4397129 .
personal data
SURNAME Iversen, Leslie
ALTERNATIVE NAMES Iversen, Leslie Lars (full name)
BRIEF DESCRIPTION British pharmacologist
DATE OF BIRTH October 31, 1937
PLACE OF BIRTH Exeter
DATE OF DEATH July 30, 2020