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(12) United States Patent (10) Patent No.: US 8,039,468 B2 Greer (45) Date of Patent: Oct

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(12) United States Patent (10) Patent No.: US 8,039,468 B2 Greer (45) Date of Patent: Oct US008O39468B2 (12) United States Patent (10) Patent No.: US 8,039,468 B2 Greer (45) Date of Patent: Oct. 18, 2011 (54) METHOD OF INHIBITION OF Denavit-Saubie et al., “Effects of opiates and methionine-enkephalin RESPRATORY DEPRESSIONUSING on pontine and bulbar respiratory neurones of the cat.” 1978, Brain POSITIVE ALLOSTERICAMPARECEPTOR Res., 155(1):55-67. MODULATORS Feldman et al. “Looking for inspiration: new perspectives on respi ratory rhythm.”2006, Nat. Rev. Neurosci., 7(3):232-24. (75) Inventor: John Greer, Edmonton (CA) Funk, G.D., et al. "Generation and transmission of respiratory oscil lations in medullary slices: role of excitatory amino acids.” (1993).J. (73) Assignee: The Governors of the University of Neurophysiol. 70(4): 1497-1515. Funk, G.D., et al. “Modulation of neural network activity in vitro by Alberta, Edmonton, AB (CA) cyclothiazide, a drug that blocks desensitization of AMPA receptors' 1995, J. Neurosci., 15:4046-4056. (*) Notice: Subject to any disclaimer, the term of this Goff, D.C., et al. "A placebo-controlled pilot study of the ampakine patent is extended or adjusted under 35 CX516 added to clozapine in schizophrenia.” J. Clin. U.S.C. 154(b) by 996 days. Psychopharmacol., 21(5):484-487. Greer J.J., et al. “Role of excitatory amino acids in the generation and (21) Appl. No.: 11/847,835 transmission of respiratory drive in neonatal rat.” 1991, J. Physiol. 437: 727-749. (22) Filed: Aug. 30, 2007 Greer, J.J., et al. Respiratory and locomotor patterns generated in the fetal rat brain stem-spinal cordinvitro, J. Neurophysiol., 67:996-999. (65) Prior Publication Data Horneret al., “Update in Sleep and Control of Ventilation.” 2007, Am. J. Respir. Crit. Care Med. 175, 426-431. US 2008/O26 1962 A1 Oct. 23, 2008 Johnson et al. “Modulation of respiratory rhythmin vitro: role of Gi/o protein-mediated mechanisms,” 1996, J. Appl. Physiol. 80(6):2120 Related U.S. Application Data 33. Lauterbornet al. "Positive Modulation of AMPA Receptors Increases (60) Provisional application No. 60/824.245, filed on Aug. Neurotrophin.” 2000, J. Neurosci. 20:8-21. 31, 2006. Lynch “Glutamate-based therapeutic approaches: ampakines. 2006, Curr: Op. Pharmacol. 6:82-88. (51) Int. Cl. Nagarajan et al. “Mechanism and impact of allosteric AMPA receptor A 6LX3/5377 (2006.01) modulation by the ampakine CX546, 2001, Neuropharmacol., A6 IK3I/435 (2006.01) 41:650-663. A 6LX3L/357 (2006.01) Ren et al., “Ampakines Alleviate Respiratory Depression in Rats.” (52) U.S. Cl. ...................... 514/231.5: 514/315; 514/453 2006, Am. J. Respir. Crit. Care Med., 174, 1384-1391. Shook et al., “Differential roles of opioid receptors in respiration, (58) Field of Classification Search ............... 514/231.5, respiratory disease, and opiate-induced respiratory depression.” 514/315,453 1990, Am. Rev. Respir. Dis., 142(4):895-909. See application file for complete search history. Thoby-Brisson et al. “Expression of Functional Tyrosine Kinase B Receptors by Rhythmically Active Respiratory Neurons in the Pre (56) References Cited Bötzinger Complex of Neonatal Mice.” 2003, J. Neurosci., 23:7685 T689. U.S. PATENT DOCUMENTS Whitney et al., “AMPA Glutamate Receptors and Respiratory Con 6,730,677 B2 * 5/2004 Rogers et al. ............ 514,254.03 trol in the Developing Rat: Anatomic and Pharmacological Aspects.” 6,943,159 B1 9, 2005 Gouliaev et al. 2000, Am. J. Physiol. Regulatory Integrative Comp. Physiol. 278: 7,026.475 B2 4/2006 Ceci et al. R520-528. 2002fOO55508 A1 5/2002 Rogers et al. 2004/0082519 A1 4/2004 Hedner et al. * cited by examiner 2006/0276532 Al 12/2006 Dominguez-Manzanares Primary Examiner — Jeffrey S Lundgren FOREIGN PATENT DOCUMENTS Assistant Examiner — Nelson Blakely, III WO WO94/O2475 A1 2, 1994 WO WO 98.3595.0 A1 8, 1998 (74) Attorney, Agent, or Firm — Kilpatrick Townsend & Stockton LLP OTHER PUBLICATIONS (57) ABSTRACT Ge et al. (Journal of Physiology, vol. 509.1, pp. 255-266; 1998).* Sebel et al. (British Medicla Journal, vol. 289, pp. 1581-1582; The invention is directed to a method for alleviating respira 1984).* tory depression in a subject as a result of disease of pharma Looi-Lyons etal. (Journal of Clinical Anesthesia, vol. 8, pp. 151-156; cological agents such as opiates, opioids or barbiturates. The 1996).* invention also discloses pharmaceutical compositions for use Arai, et al. “Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus.” 2004.m. with the method, the composition containing in combination, Neurosci., 123(4): 1011-1024. an analgesic, anaesthetic, or a sedative and a positive allos Bissonnette et al., “Non-NMDA Receptors Modulate Respiratory teric AMPA receptor modulator in an amount sufficient to Drive in Fetal Sheep.” 1997, Journal of Physiology, 50.1.2, 415-423. reduce or inhibit respiratory depression caused by the anal Black, “Therapeutic potential of positive AMPA modulators and their gesic, anaesthetic, or sedative. relationship to AMPA receptor subunits. A review of preclinical data.” 2005, Psychopharmacol., 179, 154-163. 11 Claims, 12 Drawing Sheets U.S. Patent Oct. 18, 2011 Sheet 1 of 12 US 8,039,468 B2 Control el-III III. CX546 (50M) LILLILLIII III. ILLILLILLIllCX546 (100M) Washout Ill-ll 10S FIG. 1A ... Control U.S. Patent Oct. 18, 2011 Sheet 2 of 12 US 8,039,468 B2 XIIIH 3. Atti a- b- C- d 60s CX546 (400 uM) l b 10s FIG. 2A -- al | -o- CX546(400M) If, or Control Time (min) FIG. 2B U.S. Patent Oct. 18, 2011 Sheet 3 of 12 US 8,039,468 B2 Brainstem-spinal Cord Medullary slice Control Control DAGO (800 nM) DAGO (800 nM) CX546 (200uM) CX546 (200M) 0s. FIG. 3A FIG. 3B c- DAGO (800 nM) c= DAGO (800 nM) s CX546 (200LM) es CX546 (200uM) 1.0 O 80.8 5 SO6 9 90.4 g ces CD 0.2 500 2 - Brainstem- Medullary C Brainstem- Medullary spinal COrd slice spinal Cord slice FIG. 3C FIG. 3D U.S. Patent Oct. 18, 2011 Sheet 4 of 12 US 8,039,468 B2 Fentany 4nM CX54650M t ... ". ." Control Fenlanyl 4nM Peak CX546 CX54650 CX54650" effect uM5min uM 10min FIG. 4A 1.5 - - - - amplitude I- - frequency - - J. - rt 0.5 Old-Control -----------Fentany man- 4nM--- Cx546 ------CX5465OuM --- CX546 5min 5min peak effect 5min 5OUM 1 Omin FIG. 4B U.S. Patent Oct. 18, 2011 Sheet 5 of 12 US 8,039,468 B2 FIG. 5A FIG. 5D Control Respiration depreSSant M 10 m CX546 (16mg/kg) Fentanyl (60 ug/kg) -W------- CX546 (16 mg/kg) AMRAAMMA Fentanyl Phenobarbital (60 g/kg) (28 mg/kg) FIG. 5B FIG. 5E Control Respiration depressant m CX546 (16 mg/kg) MMM) 10 Phenobarbital (28 mg/kg) O.8 i 0.6 CX546 (16 mg/kg) 0.4 MWWAMAM 0.2 0.0 Fentanyl Phenobarbital (60 g/kg) (28 mg/kg) FIG. 5C Control FIG. 5F MMYMMA - Fentany m CX546 (16 mg/kg) Fentanyl (130pug/kg) S 12 12 i WWWW, i.9. 3O 1.0 CX546 (16 mg/kg)mg/Kg g 08 . 0.8 0.6 0.6 0.2 E02 1S O 0.0 0.0 U.S. Patent Oct. 18, 2011 Sheet 6 of 12 US 8,039,468 B2 OÀILIANIEIÐ?!\/HOSICIANOL\/>|lc|SER!HONOISSERHdcITISCIE?OTICINI-OS)INV/C1 0 ENITOHdHOIN(IANOEMVOTA-9-NVZV-In-HOZNEE)-v-IONOILOBITNI SELVIAETTVOLQ8E-ldEHLOLNIV?9XOHO(WCINQOdWOO) U.S. Patent Oct. 18, 2011 Sheet 7 of 12 US 8,039,468 B2 OÀILIANIEICITÀLITc||NWXNOLVNo.lidSER!HONOISSERHddTISCIE?OTICINI-OSOINV/C) // SELVIAETTVSnHTonNIIXHHLOLNIV?9XOHO(WCINñOdlNO3) ENITOHdHOIN(IANO@IVOTA-G-NVZwºln-IOZNEE)-VBONOILOETNI | [IX] U.S. Patent Oct. 18, 2011 Sheet 8 of 12 US 8,039,468 B2 |||||!!!!!!!!!!!!!!!!!!!!!!!!!“…| SLNEHMImONOy?9XOQNV(VCINñOdWIOO)ENITOHdHOW(TÅNORHVOT? -G-NVZVºn-HOZNEE)-y-IONOILVOITddVHLVÆHOSLOE-I-JE EIHLOLNIELVINVILT?TS)HONOLLV/O|Tc|d\/TV/OOTÅ8CIE?OTICINI XLILHOEKONEISERICHEIHLNISTIETOTINITX X_LL U.S. Patent Oct. 18, 2011 Sheet 9 of 12 US 8,039,468 B2 (WnOOL)VpunoduuOO+(Nng'O)XLLNI q=JonqNISLNEMHITONO(VCINQOdWOO)ENITOHdHOW(TÅNORMVOT? XLLHOEKONEISERJdEHLNIXEITd|WOO -9-NVZVAJ/m-IOZNEE)-vHONOILVOITddVHLV8-IOSLOBH-IE ME?NIZLQ8BºldHHLOLNIBLWWW.LmT9-IONOILVOITddwTVOOTÅ8 (WnG’O)XLLNI 0, U.S. Patent Oct. 18, 2011 Sheet 10 of 12 US 8,039,468 B2 AUL OC 03SG qnouse/WWdo0;9:79XO|Ou?uOO olgaa?id-Nollow?9x9xodos?SATvNwNo.w'?nTTEOVALNI ————————— TTTTTTTT E ||----------------#79 U.S. Patent Oct. 18, 2011 Sheet 12 of 12 US 8,039,468 B2 CX614 ALLEVIATES FENTANY - NDUCED SUPPRESSION OF BREATHING IN VIVO Control d MAN O Ui 1 Fentany (130 g/kg i.p.) YWYAHAAA' FIG. 12 US 8,039,468 B2 1. 2 METHOD OF INHIBITION OF underlying cellular mechanisms responsible for the opiate RESPRATORY DEPRESSIONUSING effects on respiration have not, however, been elucidated. POSITIVE ALLOSTERICAMPARECEPTOR Opiate agents are widely used in medicine. Because they MODULATORS depress breathing, however, their use is contraindicated in many instances, especially in patients with compromised car CROSS-REFERENCES TO RELATED diovascular and pulmonary function. Thus, there has been a APPLICATIONS long-felt need to harness the analgesic power of the opiates and opioids, without depressing the respiratory function of This application claims benefit of U.S. Provisional Appli the patient. 10 The present invention addresses this and other needs by cation No. 60/824.245, filed Aug. 31, 2006, which is herein disclosing that positive allosteric AMPA receptor modulators incorporated by reference in its entirety. provide a novel pharmacological means of countering respi FIELD OF THE INVENTION ratory depression. The present invention demonstrates that a positive allosteric AMPA receptor modulator, which can 15 potentiate AMPA receptor-mediated currents (Nagarajan, N., The invention is directed towards a method for reducing or et al. (2001) Neuropharmacol. 41:650-663) is an effective inhibiting respiratory depression (RD) in a Subject as a result means of countering respiratory depression.
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