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United States Patent (19) 11 Patent Number: 5,902,815 Olney Et Al

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United States Patent (19) 11 Patent Number: 5,902,815 Olney Et Al USOO5902815A United States Patent (19) 11 Patent Number: 5,902,815 Olney et al. (45) Date of Patent: May 11, 1999 54 USE OF 5HT2A SEROTONIN AGONISTS TO Hougaku, H. et al., “Therapeutic effect of lisuride maleate on PREVENT ADVERSE EFFECTS OF NMDA post-stroke depression” Nippon Ronen Igakkai ZaSShi 31: RECEPTOR HYPOFUNCTION 52-9 (1994) (abstract). Kehne, J.H. et al., “Preclinical Characterization of the Poten 75 Inventors: John W. Olney, Ladue; Nuri B. tial of the Putative Atypical Antipsychotic MDL 100,907 as Farber, University City, both of Mo. a Potent 5-HT2A Antagonist with a Favorable CNS Saftey Profile.” The Journal of Pharmacology and Experimental 73 Assignee: Washington University, St. Louis, Mo. Therapuetics 277: 968–981 (1996). Maurel-Remy, S. et al., “Blockade of phencyclidine-induced 21 Appl. No.: 08/709,222 hyperlocomotion by clozapine and MDL 100,907 in rats reflects antagonism of 5-HT2A receptors' European Jour 22 Filed: Sep. 3, 1996 nal of Pharmacology 280: R9–R11 (1995). 51) Int. Cl. ........................ A61K 31/445; A61K 31/54; Olney, J.W., et al., “NMDAantagonist neurotoxicity: Mecha A61K 31/135 nism and prevention,” Science 254: 1515–1518 (1991). 52 U.S. Cl. .......................... 514/285; 514/315; 514/318; Olney, J.W., et al., “Glutamate receptor dysfunction and 514/646 schizophrenia.” Arch. Gen. Psychiatry 52:998-1007 (1995). 58 Field of Search ............................. 514/285; 314/315, Pulvirenti, L. et al., “Dopamine receptor agonists, partial 314/318, 646 agonists and psychostimulant addiction' Trends Pharmacol Sci 15: 374-9 (1994). 56) References Cited Robles, R.G. et al., “Natriuretic Effects of Dopamine Agonist Drugs in Models of Reduced Renal Mass” Journal of U.S. PATENT DOCUMENTS Cardiovascular Pharmacology 22 (Suppl. 2): S88-S92 5,034,400 7/1991 Olney ...................................... 514/315 (1993). 5,474,990 12/1995 Olney et al. .. ... 514/226 5,605,911 2/1997 Olney et al. .. ... 514/315 (List continued on next page.) 5,629,307 5/1997 Olney et al. ............................ 514/226 Primary Examiner Keith D. MacMillan OTHER PUBLICATIONS Attorney, Agent, or Firm Patrick D. Kelly Caldwell, M.A. et al., “The dopamine agonists lisuride and 57 ABSTRACT piribedil protect against behavioural and histological changes following 4-vessel occlusion in the rat, Neurop This invention relates to a new method for treating or Sychobiology 34: 117–24 (1996). preventing brain damage caused by NMDA receptor hypo Calne, D.B. "Initiating treatment for idiopathic parkin function (NR/hypo), using drugs such as lisuride which sonism” Neurology 44: S19-S22 (1994). Stimulate (agonize) activity at the 5HT2A class of Serotonin Carlsson, M.L. “The selective 5-HT2A receptor antagonist receptors, but which do not cause hallucinations. Data MDL 100,907 counteracts the psychomotor stimulation disclosed herein indicate that stimulation of both 5HT2A ensuing manipulations with manoaminergic glutamatergic and 5HT2C receptors causes hallucinations, while stimula or muscarinic neurotransmission in the mouse-implica tion of 5HT2A receptors but not 5HT2C receptors does not. tions for psychosis” Journal of Neural Transmission 100: Accordingly, to be useful herein, non-hallucinatory 5HT2A 225-237 (1995). agonists should either (1) antagonize (Suppress) activity at Eblen, F. et al., “Effects of 7-nitroindazole, 5HT2C receptors, or (2) have no significant effect on NG-nitro-L-arginine, and D-CPPene on harmaline-in activity at 5HT2C receptors. Selective non-hallucinatory duced postural tremor, N-methyl-D-aspartate-induced Sei 5HT2A agonists can be used in either of two treatment Zures, and lisuride-induced rotations in rats with nigral methods disclosed herein. 6-hydroxydopamine lesions,” Eur J Pharmacol 299 : 1-3 (1996). One Such treatment comprises administering a 5HT2A Fink, H. et al “Locomotor effects of lisuride: A consequence receptor agonist as a “Safener drug' which accompanies an of dopaminergic and Serotonergic actions' Psychoparma NMDA antagonist drug that is being used for a therapeutic cology 85: 464–468 (1985). purpose. Fiorella, D. etal, Role of 5-HT2A and 5-HT2C receptors in the Stimulus effects of hallucinogenic drugs. II: Reassess Another method disclosed herein involves the use of a ment of LSD false positives. Psychoparmacology 121: 5HT2A agonist drug, by itself, to combat a naturally 357–63 (1995) (abstract). occurring form of NMDA receptor hypofunction which Glennon, R.A. “Do Classical Hallucinogens Act AS 5-HT2 occurs in people Suffering from Schizophrenia. Although Agonists of Antagonists? NeuropSychopharmacology 3: 5HT2A agonists would not be optimally effective in treating long-standing cases of chronic Schizophrenia, where patho 509-517 (1990). logical changes in the brain have already reached maximal Heinz, A. et al., “Clinical aspects and follow-up of dopami or Severe levels, 5HT2A agonists can be administered early ne-induced psychoses in continuous dopaminergic therapy in the illness, Such as at the first Signs of Schizophrenic and their implications for the dopamine hypothesis of illness, and continuously thereafter to prevent the develop schizophrenic symptoms” Nervenarzt 66: 662-9 (1995) ment or worsening of pathological brain dysfunction and the (abstract). resulting psychosis. Heinz, A. et al., “Continuous Subcutaneous lisuride infusion in OPCA” Journal of Neural Transmission 90: 145–150 (1992). 14 Claims, 3 Drawing Sheets 5,902,815 Page 2 OTHER PUBLICATIONS Stocchi, F. et al., “Apomorphine and Lisuride Infusion” Rosenfeld, M.R. et al., “The Interaction of Lisuride, and Advances in Neurology 60: 653–655 (1993). Ergot derivative with Serotonergic and Dopaminergic Varty, G.B. et al. "Reversal of a dizocilpine-induced dis Receptors in Rabbit Brain” The Journal of Pharmacology ruption of prepulse inhibition of acoustic Startle response and Experimental Therapeutics 216:526-531 (1980). by the 5-HT2 receptor antagonist ketanser' European Jour Schmidt, C.J. et al., “The role of 5-HT2A receptors in nal of Pharmacology 287: 201-205 (1995). antipsychotic activity” Life Sciences 56: 2209–2222 (1995). Chemical Abstracts AN 1992:563764, Wachtel et al., 1992. U.S. Patent May 11, 1999 Sheet 1 of 3 5,902,815 V U.S. Patent May 11, 1999 Sheet 3 of 3 5,902,815 Fig. 3 100 2. 9O 75 5 D p 50 . 5 5 25 CS C 9) E O CD S C) -25 DOSe of DOl (mg/kg, intraperitoneal) O MK-801 plus DOl A MK-801 plus DOI plus ritanserin 5,902,815 1 2 USE OF 5HT2A SEROTONIN AGONSTS TO example, they may either include or exclude various addi PREVENT ADVERSE EFFECTS OF NMDA tional components, Such as an ion channel which is opened RECEPTOR HYPOFUNCTION or closed by a receptor. Upon being activated (excited) by the glutamate GOVERNMENT SUPPORT molecule, the glutamate receptor changes its conformation, The research which led to this invention was supported in in a manner which briefly opens an ion channel that Serves part by grants from the National Institutes of Health, includ as a conduit through the cell membrane. Calcium (Ca"), ing grants AG 11355, DA05072, DA00290, and MH 38894. Sodium (Na"), and certain other types of ions immediately Accordingly, the federal government has certain rights in flow through the ion channel, thereby altering a chemical this invention. ionic gradient that normally exists acroSS the membrane of the neuron. This activates the neuron, causing it to release its BACKGROUND OF THE INVENTION own neurotransmitters at other (“downstream”) Synapses, The present invention relates to neurology and thereby transmitting nerve Signals to Still other neurons. pharmacology, and to drugs for treating or preventing prob To reset the mechanism and get both the transmitting lems in the central nervous system (CNS). More specifically, 15 neuron and the receiving neuron back to a resting/ready this invention involves drugs that activate a certain type of condition, where both are ready to handle another nerve receptor in the brain which is normally activated by Sero Signal, the ion channel quickly closes, and the glutamate tonin. This receptor is called the 5HT2A receptor. receptor protein on the Signal-receiving neuron releases the The following Background Sections provide introductory glutamate molecule. The glutamate molecule floats back into the Synaptic fluid between the neurons, and a molecular information on Several types of receptors on the Surfaces of transport System quickly intercepts it and transports it back neurons inside the brain, and on various neurotransmitters and drugs that Stimulate or Suppress activity at these recep inside the transmitting neuron. The Signal-receiving neuron tors. Although the drugs that are the Subject of this invention activates a Set of molecular pumps, which rapidly transport Stimulate certain Serotonin receptors, these drugs are calcium and Sodium ions (which had entered the cell though intended to solve problems involving an entirely different 25 the glutamate-controlled ion channel) back out of the neuron class of receptors, triggered by glutamate. Therefore, to regain a “polarized” condition, So that it will be ready to glutamate receptors are described first, followed by Seroto receive another nerve Signal. nin receptors. This entire Set of chemical actions-release of glutamate by a transmitting neuron, activation and depolarization of a Glutamate (GLU) and Its Receptors, Agonists and Signal-receiving neuron, release of the glutamate transmitter Antagonists molecule by the receptor protein, clearance of the free Glutamate (sometimes abbreviated as GLU) is one of the glutamate from the Synaptic fluid, and restoration of the 20 common amino acids used by all living cells to make polarized/ready State in the signal-receiving neuron-is protein. Glutamate is the ionized form of glutamic acid, and extraordinarily rapid. All of these Steps, together, occur is the predominant form in neutral Solutions, at pH 7. 35 within a few milliseconds. Since glutamate is an amino acid that can function as an In addition to its role as a building block in proteins, excitatory neurotransmitter inside the brain, it is often called glutamate also plays an entirely distinct and crucial role in an “excitatory amino acid' (EAA).
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