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(12) United States Patent (10) Patent No.: US 8,877,802 B2 Caron Et Al US008877802B2 (12) United States Patent (10) Patent No.: US 8,877,802 B2 Caron et al. (45) Date of Patent: Nov. 4, 2014 (54) ANTIPARKINSONIAN ACTION OF Lebsanft HB et al. 3.4-methylenedioxymethamphetamine counter PHENYLSOPROPYLAMINES acts akinesia enantioselectively in rat rotational behavior and catalepsy. Synapse. 2005; 55: 148-155. (75) Inventors: Marc G. Caron, Hillsborough, NC Sotnikova TD et al. DDD mice, a novel acute mouse model of (US); Tatyana D. Sotnikova, Chapel Parkinson's disease. Neurology. 2006; 67: S12-S17. International Search Report for PCT/US 05/29096, Aug. 3, 2007. Hill, NC (US); Raul R. Gainetdinov, Parkes, JD, et al., Amphetamines in the treatment of Parkinson's Chapel Hill, NC (US) disease, Journal of Neurology, Neurosurgery, and Psychiatry (1975), pp. 232-237, vol. 38. (73) Assignee: Duke Univerity, Durham, NC (US) Beasley, B. L., et al., Fenfluramine Hydrochloride Treatment of Parkinsonism, Arch Neurol (Apr. 1977) pp. 255-256, vol. 34. (*) Notice: Subject to any disclaimer, the term of this Beasley, B, Fenfluramine and Parkinson's Disease, Letters to the patent is extended or adjusted under 35 Editor, Arch Neurol (Nov. 1977) p. 720, vol. 34. U.S.C. 154(b) by 2413 days. Karoum, F, et al., Metabolism of (-) deprenyl to amphetamine and methamphetamine may be responsible for deprenyl's therapeutic (21) Appl. No.: 11/460,046 benefit: A biochemical assessment, Neurology (May 1982), pp. 503 509, vol. 32. (22) Filed: Jul. 26, 2006 Goetz, CG, et al., Bupropion in Parkinson's disease, Neurology (Aug. 1984) pp. 1092-1094, vol. 34. (65) Prior Publication Data Wadenberg, M-L, Serotonergic Mechanisms in Neuroleptic-Induced Catalepsy in the Rat, Nueroscience and Biobehavioral Reviews US 2007/0027208A1 Feb. 1, 2007 (1996) pp. 325-339, vol. 20:2. Banjaw, MY, et al., Anticataleptic Activity of Cathinone and MDMA Related U.S. Application Data (Ecstasy) Upon Acute and Subchronic Administration in Rat, Syn apse (2003) pp. 232-238, vol. 49. (60) Provisional application No. 60/703,137, filed on Jul. Sotnikova, TD, et al., Dopamine-Independent Locomotor Actions of 28, 2005. Amphetamines in a Novel Acute Mouse Model of Parkinson Disease, PloS Biology (Aug. 2005) pp. 1-13, vol. 3:8 e271. (51) Int. Cl. Request for Applications, Unmet Needs for Treating Symptoms of A6 IK3I/36 (2006.01) Parkinson's Disease DOPA Non-Responsive Symptoms of PD, The A6 IK3I/35 (2006.01) Michael J. Fox Foundation for Parkinson's Research (Mar. 13, 2006) A6 IK3I/37 (2006.01) pp. 1-7. (52) U.S. Cl. International Preliminary Report on Patentability, Written Opinion CPC ............... A6 IK3I/137 (2013.01); A61 K3I/36 for PCT/US06/29096, Jan. 29, 2008. Seiden LS et al. Amphetamine: effects on catecholamine systems and (2013.01) behavior. Annu Rev Pharmacol Toxicol. 1993:32: 639-677. USPC ........................................... 514/464; 514/649 Sulzer D et al. Amphetamine redistributes dopamine from Synaptic (58) Field of Classification Search vesicles to the cytosol and promotes reverse transport. The Journal of CPC ............................. A61K 3 1/36; A61K 31/137 Neuroscience. May 1995; 15(5): 4102-4108. USPC .......................................... 514/449, 464, 649 Fon EA et al. Vesicular transport regulates monoamine storage and See application file for complete search history. release but is not essential for amphetamine action. Neuron. Dec. 1997; 19: 1271-1283. (56) References Cited Jones SR et al. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. The Journal of Neuroscience. Mar. U.S. PATENT DOCUMENTS 15, 1998; 18(6): 1979-1986. Amphetamine. Wikipedia. Retrieved Mar. 10, 2011. 17 pp. 3,547,999 A 12/1970 Shulgin et al. 3,933,911 A 1, 1976 Main * cited by examiner 4,034,113 A 7/1977 Shulgin 4,105,695 A 8/1978 Partyka et al. 4,758,571 A * 7/1988 Curtius et al. ................ 514,249 Primary Examiner — Jennifer M Kim 5,866,756 A 2f1999 Giros et al. (74) Attorney, Agent, or Firm — Myers Bigel Sibley & 6,218,595 B1 4/2001 Giros et al. Sajovec, P.A. 6,797,732 B2 9, 2004 Virkki et al. 2004/O147613 A1 7/2004 Dawirs (57) ABSTRACT 2005/0059743 A1 3/2005 Epstein et al. 2006/0241082 A1 10, 2006 Fleckenstein et al. A method of treating a subject for Parkinson's disease com OTHER PUBLICATIONS prises administering said Subject a phenylisopropylamine in an amount effective to treat said Parkinson's disease. In some Lebsanft. MDMA ("Ecstasy”) in Tiermodellen des Morbus embodiments the method is used to treat at least a motor Parkinson Universitat Tubingen, 15 Fakultat fur Biologie Oct. 27. symptom of Parkinson's disease; in Some embodiments the 2004 pp. 1-2.* method is used to treat at least a non-motor symptom of STN database Registry Nov. 16, 1984. Ecstasy, 42542-10-9/rn.* Parkinson's disease. Schmidt WJ et al. Ecstasy counteracts catalepsy in rats, an anti parkinsonian effect? Neuroscience Letters. 2002; 330: 251-254. 14 Claims, 11 Drawing Sheets U.S. Patent Nov. 4, 2014 Sheet 1 of 11 US 8,877,802 B2 S. S si s r le t it as s s E se Fo to t r w o4-----or.: Nd s g g 3 (soluoo Jo 9.) (soluogo '6) wo enss Ieens an enssp. xauoo requold O 3 c s s p se l o to t t ( et c ga (enSSE eM Sufu) C co C WCenSS3 eers (enssen fufu) < 3Nansspxeuoo buoy U.S. Patent Nov. 4, 2014 Sheet 2 of 11 US 8,877,802 B2 : s i 8 s al N C - N vie wn r (eAeeseq go.) WOleInleoeye eye-13S : sg 3 -b-i s to a to E to N s s N wn tal (eAe reseq go 9.) LL Woleneoexe feels U.S. Patent US 8,877,802 B2 (£JoI)Z9.In??H U.S. Patent US 8,877,802 B2 -------- (sdes go equanu) L 5uoei (oes) poi et uo gueds eup “fudsels U.S. Patent US 8,877,802 B2 (eIOOS) xeye fulfil U.S. Patent US 8,877,802 B2 U.S. Patent US 8,877,802 B2 U.S. Patent Nov. 4, 2014 Sheet 10 of 11 US 8,877,802 B2 CMT (250 nigkg, i.p.) B 2. ot (250 mgkg, i.p.) 2 | (+)-MDMA i 150 y t 30 mg/kg 60 g/kg i.p. EE +)-MDMA 100 mg/kgi.p.) 1000 S. a - - - TI s 500 re Y y 2015D to 210 o; . Time (min) Tine (min) C 40 D raya 'la MT (250 mg/kg, i.p.) is 5 at S 100 S. i (+)-MDMA t 2 is?o (100 mg/kg, i.p.) O 50 Se 8. O 6, 2 8 24t S 8) 10 OO (+)-MDMA (mg/kg, i.p.) antagonistsr)2A Time in ) E 3. re: as - - --N t 5 E. wer 5 so; g 20 g so: rr t E 10 : O-, - - - - - - - "Ari" (+)-MDMA (mg/kg) +L-DOPACO (Of 10 mg/kg) Drug (irgi'kg+l-DOPACE) (100 mg/kg) Figure 5 U.S. Patent Figure 6 US 8,877,802 B2 1. 2 ANTIPARKINSONIAN ACTION OF precursor, L-DOPA, has been used for many years and PHENYLSOPROPYLAMINES remains the gold standard for treatment of PD22.23. How ever, the efficacy of this treatment wanes with time, and RELATED APPLICATIONS fluctuations in motor performance as well as psychotic reac tions and dyskinesias often develop. DA agonists, as well as This application claims the benefit of U.S. provisional several other classes of drugs directly or indirectly affecting patent application Ser. No. 60/703,137, filed Jul. 28, 2005, the DA function (monoamine oxidase MAO inhibitors, COMT disclosure of which is incorporated by reference herein in its catechol-O-methyl transferase inhibitors, and amantadine), entirety. have some beneficial effects in PD patients, but they are This invention was made with government Support under 10 mostly used either at early stages of PD or are applied as grant nos. NS-19576 and MPH-40159 from the National adjunct medications to enhance the benefits of L-DOPA 21, Institutes of Health. The US Government has certain rights to 24.25. Due to these limitations of existing therapeutic this invention. approaches, the development of better anti-Parkinsonian drugs remains a major objective of PD research. FIELD OF THE INVENTION 15 Several lines of evidence suggest that development of novel non-dopaminergic approaches aimed at bypassing The present invention concerns methods of treating Par impaired dopaminergic transmission would be beneficial in kinson's disease with phenylisopropylamines. PD, particularly at later stages 16.26-28, however it is still unclear if these treatments would just potentiate action of BACKGROUND OF THE INVENTION residual DA or act completely independently of DA. A num ber of animal models of DA deficiency, based on pharmaco The phenylethylamine derivative dopamine (DA) is criti logic, neurotoxic, or genetic approaches, have been devel cally involved in a wide variety of vital functions such as oped to understand basic pathological processes leading to locomotion, feeding, emotions and reward 1-3. Major DA PD and/or to search for novel principles of therapy (29-36. systems in the brain originate from brainstem DA neurons 25 However, in rodents, the prolonged absence of DA is not located in the Substantia nigra pars compacta (SNc) and the compatible with life 3,7,8, and animals with chronic severe ventral tegmental area (VTA). SNc neurons project mainly to DA depletion are generally not available for routine experi the caudate/putamen or dorsal striatum (nigrostriatal system), mentation. whereas VTA neurons send their axons to the ventral striatum We have developed mice lacking the functional DAT (DAT including the nucleus accumbens, as well as certain other 30 KO mice) 11 that display remarkable alterations in the limbic (mesolimbic system) and cortical areas (mesocortical compartmentalization of DA 12,13.37.
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