Excitatory Amino Acids: Clinical Results with Antagonists

171 Pages·1997·13.99 MB·English

by  Paul L. Herrling

Excitatory Amino Acids- Clinical Results with Antagonists
Every effort has been made by the author and the publisher of the book to ensure that dosage recommendations are
correct and in agreement with standards officially accepted at the time of publication.
It does happen, however, that dosage schedules are changed from time to time in the light of accumulating clin-
ical experience and continuing laboratory studies. This is most likely to occur in the case of recently introduced
products.
It is urged, therefore, that you check the manufacturer's recommendations for dosage, especially if the drug to be
administered or prescribed is one that you use only infrequently or have not used for some time.
THE PUBLISHER
Excitatory Amino Acids-
Clinical Results with Antagonists
Edited by
P.L. HERRLING
Head of Corporate Research,
Sandoz Pharma, Basle, Switzerland
ACADEMIC PRESS
Harcourt Brace & Company, Publishers
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Copyright (cid:14)9 1997 by ACADEMIC PRESS
All Rights Reserved.
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Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Selfotel (CGS 19755) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
M. Schmutz, A. Arthur, H. Faleck, G. Karlsson, A. Kotake, L. Lantwicki, L. LaRue, S. Markabi,
D. Murphy, M. Powell and D. Sauer
1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 Overview of the pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Physical and chemical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Preclinical pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 Rationale for clinical testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4 Human results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Healthy volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3 Patients undergoing craniotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4 Patients with acute ischemic stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5 Patients with traumatic brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
o-CPPene (SDZ EAA-494)--A Competitive NMDA Antagonist: Pharmacology and Results in Humans
P. L. Herrling, M. Emre and J. C. Watkins
1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2 Structure-activity relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3 General pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.1 Specificity in binding assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.2 Functional assays in vitro ...................................... 12
3.3 Characterization of D-CPPene in whole animals .......................... 13
4 Human studies ................................................ 17
4.1 Subjects and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Intrathecal Administration of a Competitive NMDA Receptor Antagonist for Pain Treatment ...... 23
J. D. Kristensen
1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2 Overview of the pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3 Rationale for clinical testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.1 Neurotransmitters for excitatory nociceptive signals ........................ 24
3.2 Neuronal plasticity, the NMDA receptor, and pain ......................... 24
3.3 Implications for clinical pain and its treatment ........................... 25
4 Human results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.1 Inhibition of glutamate release .......... ......................... 27
vi CONTENTS
5.2 Antagonizing the NMDA receptor sites ............................... 27
5.3 Antagonizing the effects of NMDA receptor activation ...................... 29
5.4 Interaction with other receptor systems ............................... 29
Clinical Experience with the NMDA Ion Channel Blocker, Aptiganel Hydrochloride (CERESTAT*) 31
A. G. Knapp, L. I. Mathews and E. R. Gamzu
1 Summary .................................................. 31
2 Pharmacology ............................................... 32
2.1 Site and mechanism of action .................................... 32
2.2 General in vivo pharmacology .................................... 32
2.3 In vitro and in vivo neuroprotection ................................. 33
2.4 Toxicology .............................................. 33
2.5 Pharmacokinetics and metabolism ................................. 33
3 Clinical studies in normal male volunteers ................................. 34
4 Clinical studies in patients ......................................... 34
4.1 Stroke 34
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Severe traumatic brain injury .................................... 38
5 Discussion ................................................. 41
Development of ACPC, A Partial Agonist of the Glycine Site on the NMDA Receptor ......... 43
M-L. Maccecchini
1 Introduction ................................................ 43
2 Partial agonism as a therapeutic approach ................................. 43
3 ACPC - pharmacology and mechanism of action ............................. 44
4 Efficacy of ACPC in animal models of neuroprotection .......................... 44
4.1 Global and focal ischemia ...................................... 45
4.2 Spinal cord injury .......................................... 47
5 Efficacy of ACPC in animal models of depression and anxiety ...................... 48
5.1 Antidepressant activity ....................................... 48
5.2 Anxiolytic activity .......................................... 49
6 Prevention of opiate tolerance and toxicity by ACPC ........................... 49
7 Pharmacokinetics .............................................. 50
8 Safety profiles of ACPC in animal models ................................. 52
9 PCP-like effects .............................................. 53
10 Phase I clinical trials of ACPC ....................................... 54
Ifenprodil and Eliprodil: Neuroprotective NMDA Receptor Antagonists and Calcium Channel Blockers 57
C. Carter, P. Avenet, J. Benavides, F. Besnard, B. Biton, A. Cudennec, D. Duverger, J. Frost, C. Giroux,
D. Graham, S. Z. Langer, J. P. Nowicki, A. Oblin, G. Perrault, S. Pigasse, P. Rosen, D. Sanger,
H. Schoemaker, J. P. Th~not and B. Scatton
1 Introduction ................................................ 57
2 The NMDA receptor complex and its regulation ............................. 59
3 Actions of ifenprodil and eliprodil at different sites of the NMDA receptor ............... 59
3.1 [3H]Ifenprodil and [3H]eliprodil binding .............................. 61
3.2 Effects of ifenprodil on the glycine site ............................... 63
3.3 Effects of ifenprodil on the glutamate antagonist binding site ................... 64
3.4 Effects of ifenprodil on [3H] MK-801 binding ........................... 66
3.5 Functional consequences of allosteric interactions between the ifenprodil, glycine, and glutamate
66
sites .................................................
3.6 Selective antagonism or NMDA receptors containing the NR2B subunit ............. 67
67
3.7 NMDA receptor antagnism in vitro and in vivo ...........................
71
4 Other sites of action of ifenprodil and eliprodil ..............................
CONTENTS vii
4.1 Ifenprodil and eliprodil as t~ ligands ................................. 71
4.2 Calcium channel antagonism .................................... 72
4.3 Other receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
5 Neuroprotective effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
5.1 Neuroprotective effects in vitro ................................... 73
5.2 Neuroprotective effects in vivo ................................... 73
6 Behavioral pharmacology and side-effect profile ............................. 74
7 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
8 Clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
8.1 Phase I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
8.2 Phase II safety studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
(3S,4aR,6R,8aR)-6-[2- l(2)H-Tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic Acid (LY293558)
and its Racemate (LY215490): A Selective and Competitive AMPA/Kainate Receptor Antagonist . . . 81
D. Lodge and D. D. Schoepp
1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2 LY293558 as a novel neuroprotectant compound ............................. 81
3 In vitro glutamate receptor profile ..................................... 82
4 In vivo AMPA receptor antagonism .................................... 83
5 Effects of LY293558 on CNS excitability ................................. 83
6 In vivo neuroprotection against AMPA-induced excitotoxicity ...................... 84
7 Neuroprotectant activity in animal models of cerebral ischemia ..................... 85
8 Overview and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
The NBQX Story . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
L. Nordholm, M. Sheardown and T. Honord
1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
2.1 In vitro studies and structure-activity relationship ......................... 89
2.2 In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
2.3 Toxicity and side-effect profile ................................... 93
2.4 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
3 Human pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Riluzole in Amyotrophic Lateral Sclerosis ................................ 99
E. Louvel
1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
3 Chemical structure ............................ . ................ 100
4 Neuroprotective properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
4.1 Neuroprotective effects in vitro ................................... 100
4.2 Neuroprotective effects in vivo ................................... 100
5 Mechanism(s) of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6 Rationale of clinical testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6.1 Excitotoxic hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6.2 Survival as the clinical end-point .................................. 102
7 Clinical results .................... ........................... 102
7.1 Preliminary determination of a neuroprotective dose ........................ 102
7.2 First pivotal study in ALS ...................................... 103
viii CONTENTS
7.3 Second pivotal study in ALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
10 Preclinical and Clinical Aspects of Remacemide Hydrochloride ..................... 109
G. C. Palmer and J. B. Hutchison
1 Preclinical efficacy studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
1.1 Background and antiepileptic potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
1.2 Anticonvulsant profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
1.3 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
1.4 Neuroprotective properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
1.5 Acute and chronic safety considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
2 Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
2.1 Human volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
2.2 Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
2.3 Other patient groups ........... . ............................. 119
3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Summary Table of Compounds and Their Clinical Status ......................... 125
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Contributors
A. Arthur, Preclinical Safety, Pharmaceuticals S. Z. Langer, Synth61abo Recherche, 31 avenue Paul
Division, Ciba K-125.11.08, Basle, CH-4002, Vaillant-Couturier, 92220 Bagneux, France.
Switzerland. L. Lantwieki, Research and Development, Pharma-
P. Avenet, Synth61abo Recherche, 31 avenue Paul ceuticals Division, Ciba, Summit, NJ 07901, USA.
VaiUant-Couturier, 92220 Bagneux, France. L. LaRue, Research and Development, Pharmaceuticals
J. Benavides, Synth61abo Recherche, 31 avenue Paul Division, Ciba, Summit, NJ 07901, USA.
Vaillant-Couturier, 92220 Bagneux, France. D. Lodge, Lilly Research Centre Ltd., Eli Lilly and
F. Besnard, Synth61aboR echerche, 10 rue des Carri~res, Company, Erl Wood Manor, Windlesham, Surrey, UK.
BP248, 92405 Rueil Malmaison, France. E. Louvei, Rh6ne-Poulenc Rorer Japan, Research and
B. Biton, Synth61abo Recherche, 31 avenue Paul Development Division, 13-1, Kachidoki 1-chome,
VaiUant-Couturier, 92220 Bagneux, France. Chuo-Ku, Tokyo 104, Japan.
C. Carter, Synth61aboR echerche, 10 rue des Carfi~res, M-L. Maececehini, Symphony Pharmaceuticals, Inc.,
BP248, 92405 Rueil Malmaison, France. 3624 Market Street, Philadelphia, PA 19104, USA.
A. Cudemaee, Synth61abo Recherche, 31 avenue Paul S. Markabi, Research and Development, Pharma-
VaiUant-Couturier, 92220 Bagneux, France. ceuticals Division, Ciba, 92506 Rueil Malmaison
D. Duverger, Synth61abo Recherche, 31 avenue Paul Cedex, France.
VaiUant-Couturier, 92220 Bagneux, France. L. I. Mathews, Cambridge Neuroscience, Inc., 1
M. Emre, Clinic of Research and Development of the Kendall Square, Building 700, Cambridge, MA 02139,
Central Nervous System, Sandoz Pharma Ltd., Basle, USA.
CH-4002, Switzerland. D. Murphy, Research and Development, Pharma-
H. Faleek, Research and Development, Pharmaceuticals ceuticals Division, Ciba, Summit, NJ 07901, USA.
Division, Ciba, Summit, NJ 07901, USA. L. Nordholm, Novo Nordisk, Krogshoejvej 29, DK-
J. Frost, Synth61abo Recherche, 31 avenue Paul 2880 Bagsvaerd, Denmark.
Vaillant-Couturier, 92220 Bagneux, France. J. P. Nowicki, Synth61abo Recherche, 31 avenue Paul
E. R. Gamzu, Cambridge Neuroscience, Inc., 1 Kendall VaiUant-Couturier, 92220 Bagneux, France.
Square, Building 700, Cambridge, MA 02139, USA. A. Oblin, Synth61abo Recherche, 31 avenue Paul
C. Giroux, Synth61abo Recherche, 31 avenue Paul VaiUant-Couturier, 92220 Bagneux, France.
Vaillant-Couturier, 92220 Bagneux, France. G. C. Palmer, Department of Biology, Astra Arcus
D. Graham, Synth61abo Recherche, 31 avenue Paul USA, PO Box 20890, Rochester, NY 14602, USA.
Vaillant-Couturier, 92220 Bagneux, France. G. Perrault, Synth61abo Recherche, 31 avenue Paul
P. L. Herding, Sandoz Pharma Ltd., Basle, CH-4002, Vaillant-Couturier, 92220 Bagneux, France.
Switzerland. S. Pigasse, Synth61abo Recherche, 31 avenue Paul
T. l-Ionor6, Department of the Central Nervous System, VaiUant-Couturier, 92220 Bagneux, France.
Sandoz Pharrna Ltd., Basle, CH-4002, Switzerland. M. PoweR, Research and Development, Pharma-
J. B. Hutehison, Department of Medical Affairs, Astra ceuticals Division, Ciba, Summit, NJ 07901, USA.
Charnwood, BakeweU Road, Loughborough, P. Rosen, Synth61abo Recherche, 31 avenue Paul
Leicestershire LE11 0HR, UK. VaiUant-Couturier, 92220 Bagneux, France.
G. Karlsson, Research and Development, Pharma- D. Sanger, Synth61abo Recherche, 31 avenue Paul
ceuticals Division, Ciba K-125.11.08, Basle, CH-4002, VaiUant-Couturier, 92220 Bagneux, France.
Switzerland. D. Sauer, Research and Development, Phamaaceuticals
A. Kotake, Research and Development, Pharma- Division, Ciba K-125.11.08, Basle, CH-4002,
ceuticals Division, Ciba, Summit, NJ 07901, USA. Switzerland.
A. G. Knapp, Cambridge Neuroscience, Inc., 1 Kendall B. Seatton, Synth61abo Recherche, 31 avenue Paul
Square, Building 700, Cambridge, MA 02139, USA. VaiUant-Couturier, 92220 Bagneux, France.
J. D. Kl'istensen, Department of Anaesthesiology and M. Sdmmtz, Research and Development, Pharma-
Intensive Care, University Hospital, DK-5000 Odense, ceuticals Division, Ciba K-125.11.08, Basle, Ch-4002,
Denmark. Switzerland.