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United States Patent (19) 11 Patent Number: 6,087,376 Crooks Et Al

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United States Patent (19) 11 Patent Number: 6,087,376 Crooks Et Al US00608737.6A United States Patent (19) 11 Patent Number: 6,087,376 Crooks et al. (45) Date of Patent: *Jul. 11, 2000 54 USE OF LOBELINE COMPOUNDS IN THE Scherman, D., “Dihydrotetrabenazine binding and monoam TREATMENT OF CENTRAL NERVOUS ine uptake in mouse brain regions,” J. Neurochem. 47, SYSTEM DISEASES AND PATHOLOGIES 331-339 (1986). Scherman, D. et al., “The regionalization of Hidihydrotet 75 Inventors: Peter A. Crooks; Linda P. Dwoskin, rabenazine binding sites in the mouse brain and its relation both of Lexington, Ky. ship to the distribution of monoamines and their metabo lites.” Brain Res. 370, 176–181 (1986). 73 Assignee: University of Kentucky Research Scherman, D. et al., “HIDihydrotetrabenazine, a new in Foundation, Lexington, Ky. Vitro monoaminergic probe for human brain, J. Neurochem. 50, 1131-1136 (1988). Standaert, D.G. et al., “Treatment of central nervous system * Notice: This patent is Subject to a terminal dis degenerative disorders.” The Pharmacological Basis of claimer. Therapeutics, 9th ed. (Hardman J.G., Limberd L.E., Moli noff P.B., Ruddon R.W., and Gilman A.G., eds.), pp. 503–519, McGraw-Hill, New York (1996). 21 Appl. No.: 09/089,420 Olin, B.R. et al., “Smoking Deterrents.” In Drug Facts and Comparisons. 1995 edition, ed. by B.R. Olin et al., pp. 3087–3095, St. Loius, MO: J.B. Lippincott Co., 1995. 22 Filed: Jun. 3, 1998 Sloan, J.W. et al., “The comparative binding characteristics of nicotinic ligands and their pharmacology, Pharmacol. Related U.S. Application Data Biochem. Behav., 30:255-267 (1988). 63 Continuation-in-part of application No. 08/795,852, Feb. 5, Hamann, S.R. et al., “Hyperalgesic and analgesic actions of 1997, Pat. No. 5,830,904. morphine, U50-488, naltrexone, and (-)lobeline in the rat brainstem.” Pharmacol. Biochem. Behav., 47: 197-201 (51) Int. Cl. .............................................. A61K 31/445 (1994). 52 U.S. Cl. ............................................. 514/317; 514/331 Brioni, J.D. et al., “Nicotinic receptor agonists exhibit 58 Field of Search ...................................... 514/317,331 anxiolytic-like effects on the elevated plus-maze test, Eur: J. Pharmacol., 238:1-8 (1993). 56) References Cited Decker, M.W. et al., “Effects of lobeline, a nicotinic receptor agonist, on learning and memory, Pharmacol. Biochem. U.S. PATENT DOCUMENTS Behav., 45:571-576 (1993). 3,901,248 8/1975 Lichtneckert et al. ...................... 131/2 4,971,079 11/1990 Talapin et al. ........ ... 131/359 (List continued on next page.) 5,272,144 12/1993 Melloni et al. ...................... 514/227.5 5,403,595 4/1995 Kitchell et al. ......................... 424/501 Primary Examiner Phyllis G. Spivack 5,414,005 5/1995 Schneider et al. ... 514/343 Attorney, Agent, or Firm McDermott, Will & Emery 5,468,755 11/1995 Cincotta et al. .. ... 514/288 5,486,362 1/1996 Kitchell et al. ... ... 424/426 57 ABSTRACT 5,536,503 7/1996 Kitchell et al. ... ... 424/449 5,552,429 9/1996 Wong et al. ............. ... 514/415 Lobeline and nicotine evoke Hoverflow from rat striatal 5,576,321 11/1996 Krushinski, Jr. et al. .............. 514/255 slices preloaded with Hldopamine (HDA). The lobeline-evoked overflow is calcium-independent and not FOREIGN PATENT DOCUMENTS antagonized by mecamylamine, Suggesting a mechanism of action other than the Stimulation of nicotinic receptorS. WO92/19241 11/1992 WIPO. Whereas nicotine Stimulates nicotinic receptors, lobeline OTHER PUBLICATIONS inhibits HDA uptake into synaptic vesicles and striatal SynaptoSomes. The results Suggest that different mecha Levin, E.D., Drug Dev. Res., 38(3-4), 188-95 (abstract), nisms are responsible for the increase in Striatal DA release 1996. evoked by lobeline and nicotine. H-Dihydrotetrabenazine Barlow, R.B. et al., “Relationship between structure and HDTBZ), used routinely to probe a high-affinity binding nicotine-like activity: X-ray crystal Structure analysis of site-on the vesicular monoamine transporter (VMAT2) binds (-)cytisine and (-)lobeline hydrochloride and a comparison to vesicle membranes from rat striatum. Lobeline inhibits with (-)nicotine and other nicotine-like compounds, Br. J. HDTBZ binding with an ICs of 0.90 uM, consistent with Pharmacol., 98:799-808 (1989). its ICso of 0.88 uM for inhibition of HDA uptake into vesicles. These results Suggest that the action of lobeline is Brownstein, M.J. et al., “Neurotransmitter transporters,” Similar to that of amphetamine and that it specifically Rec. Prog. Hormone Res., 49:27-42 (1994). interacts with DTBZ sites on VMAT2 to inhibit DA uptake Debler, E.A. et al., “AScorbic acid and striatal transport of into synaptic vesicles. d-amphetamine inhibits HDTBZ H1-methyl-4-phenylpyridine (MPP) and Hldopam binding to vesicle membranes with an ICs of 39.4 uM, a ine,” Life Sci., 42:2553–2559 (1988). concentration 20 times greater than reported for inhibition of Floor, E. et al., “Dynamic Storage of dopamine in rat brain VMAT2 function, Suggesting that d-amphetamine interacts synaptic vesicles in vitro,” J. Neurochem. 64, 689-699 with a different site than lobeline on VMAT2 to inhibit (1995). monoamine uptake. These results Suggest the use of lobeline Liu Y. et al., “A molecular analysis of vesicular amine and analogs thereof in treating individuals for diseases and transporter,” Behav. Brain Res. 73, 51–58 (1996). pathologies of the central nervous System. 6,087,376 Page 2 13 Claims, 12 Drawing Sheets OTHER PUBLICATIONS Nunn-Thompson et al., “Pharmacotherapy for Smoking ceS sation.” Clin. Pharmacy., 8:710–720 (1989). Prignot, J., “Pharmacological approach to Smoking ceSSa tion,” Eur: Respir. J., 2:550–560 (1989). Kalyuzhnyy, V.V., “The treatment of nicotinism with the aid of lobeline and its influence on vegetative and vascular reactions,” J. Neural. Psychiat., 68:1864–1870 (1968). Stolerman, I.P. et al., “Dissociation between the locomotor Stimulant and depressant effects of nicotinic agonists in rats.” Psychopharmacol., 117:430-437 (1995). Fudala, P.J. et al., “Further studies on nicotine-induced conditioned place preference in the rat, Pharmacol. Bio chem. Behav., 25:1041-1049 (1986). Geller, I. et al., “Effects of nicotine monomethiodide, lobeline, chlordiazepoxide, meprobamate and caffeine on a discrimination task in laboratory rats, Psychopharmacol. (Berl), 20:355-365 (1971). Schechter, M.D. et al., “Nicotine as a discriminative cue in rats: inability of related drugs to produce a nicotine-like cuing effect,” Psychopharmacol. (Berl.), 27:379-387 (1972). Reavill, C. et al., “Behavioral and pharmacokinetics Studies on nicotine, cytosine and lobeline, Neuropharmacol., 29(7):619–624 (1990). Romano, C. et al., “Sterespecific nicotine receptors on rat brain membranes,” Science, 210:647–650 (1980). Decker, M.W. et al., “Diversity of neuronal nicotinic ace tylcholine receptors: leSSons from behavior and implications for CNS therapeutics” Life Sci., 56:545–570 (1995). Yamada, S. et al., "Brain nicotinic acetylcholine receptors biochemical characterization by neoSurugatoxin, Mol. Pharmacol., 28:120-127 (1985). Lippiello, PM. et al., “The binding of L-Hnicotine to a Single class of high affinity sites in rat brain membrane,” Mol. Pharmacol., 29:448–454 (1986). S. Martin et al., “Opioid and nicotinic medellary hyperal gesic influences in the decerebrated rat, Pharmacol Bio chem and Behav., 29 725–721 1988. Broussolle, E.P. et al., “In vivo binding of H-nicotine in the mouse brain.” Life Sci., 44:1123–1132 (1989). Bhat, R.V. et al., “Regulation of brain nicotinic receptors by chronic agonist infusion,” J. Neurochem., 56(6):1932-1939 (1991). Sakurai, Y. et al., “Enhancement of Hldopamine release and its Himetabolites in rat striatum by nicotinic drugs.” Brain Res., 242:99-106 (1982). Takano, Y. et al., “Presynaptic modulation of the release of dopamine from Striatal SynaptoSomes: difference in the effects of High K" Stimulation, methamphetamine and nico tinic drugs.” Brain Res., 279:330–334 (1983). Grady, S. et al., “Characterization of nicotine receptor-me diated H-dopamine release from Synaptosomes prepared from mouse striatum.” J. Neurochem, 59:848–856 (1992). U.S. Patent Jul. 11, 2000 Sheet 1 of 12 6,087,376 2.5 2. O 5 O 0.5 O O 20 30 40 50 60 TIME (min) FIG. (A) 0 00 Ol . 10 OO 1000 S (-) NICOTINE (uM) FIG. (B) U.S. Patent Jul. 11, 2000 Sheet 2 of 12 6,087,376 3.5 3. O 2. 5 2. O 5 1.0 0.5 O O 20 30 40 50 60 TIME (min) FIG. 2A) O 10 20 30 40 50 60 TIME (min) FIG 21B) U.S. Patent Jul. 11, 2000 Sheet 3 of 12 6,087,376 sSS s s l 2 - l ? O ad es er N pus O MOMO WWO as C C S S S C R MOAO WITWOI U.S. Patent Jul. 11, 2000 Sheet 4 of 12 6,087,376 (WiiOl)DIN DIN0?Z100)JEW+(WHOI)(Wri 0% 08 (IWSV8 HO %) SW39 WNO)W. U.S. Patent Jul. 11, 2000 Sheet 5 of 12 6,087,376 i s so o C C) Co C O N Sp CO wo r N (V1.01%) U.S. Patent Jul. 11, 2000 Sheet 6 of 12 6,087,376 (N3LONd Bu/Bu) VO s S 5 s S s s S CE CN mis 3 (N13102d Bu/6u))wdOO U.S. Patent Jul. 11, 2000 Sheet 7 of 12 6,087,376 S C Nip/ N ? H Ol C Y) o u E 9t g N 0. ? S (Wujueoud furloud) ee punO8. O ve CN O OO CO Vr CN O V. 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