USOO6403645B2 (12) United States Patent (10) Patent No.: US 6,403,645 B2 Schildkraut et al. (45) Date of Patent: Jun. 11, 2002 (54) ANTIDEPRESSANT EFFECT OF Hendley, “The Mechanism of Extraneuronal Transport of NOREPINEPHRINE UPTAKE 2 INHIBITORS Catecholamines in the Central Nervous System”, The AND COMBINED MEDICATIONS Mechanism of Neuronal and Extraneuronal Transport of INCLUDING THEM Catecholamines, Raven press, New York (1976). Inagaki et al., “Inhibitory Effect of (+)Threo-3,4-Dihy (75) Inventors: Joseph J. Schildkraut, Chestnut Hill; droxyphenylserine (DOPS) on Decarboxylation of (-)Thre John J. Mooney, Belmont, both of MA o-DOPS", Japan. J. Pharmacol., vol. 26, pp. 380-382, (US) (1976). Kato et al., “Studies on the Activity of ,-Threo-3,4-Dihy (73) Assignee: President and Fellows of Harvard droxyphenylserine (-DOPS) as a Catecholamine Precursor College, MA (US) in the Brain', Biochemical Pharmacology, vol. 36, No. 18, (*) Notice: Subject to any disclaimer, the term of this pp. 3051-3057. (1967). patent is extended or adjusted under 35 Katsube et al., “Development of L-threo-DOPS, a Norepi U.S.C. 154(b) by 0 days. nephrine Precursor Amine Acid', Yakugaku ZaSShi, vol. 144, No. 11, pp. 823–846, (1994). (21) Appl. No.: 09/811,235 Martel et al., “Comparison between uptake nd rCCT1: effects of catecholamides, metanephrines and corticoster (22) Filed: Mar. 16, 2001 one', Naunyn-Schmiedeberg's Arch Pharmacol, vol. 359, pp. 303-309, (1999). Related U.S. Application Data Maruyama et al., “A new metabolic pathway of -threo-3, (60) Provisional application No. 60/189,828, filed on Mar. 16, 4-dihydroxyphenylserine, a precursor amino acid of nore 2000. pinephrine, in the Studies by in vivo microdialysis”, J. (51) Int. Cl." ...................... A61K 31/195; A61K 31/55; Neural Transm, vol. 7, pp. 21-33, (1994). A61K 31/53; A61K 31/335; A61K 31/135 Maruyama et al., “The metabolism of ,-DOPA and -Th reo-3, 4-dihydroxyphenylserine and their effects on (52) U.S. Cl. ....................... 514/567; 514/211; 514/217; monoamines in the human brain: analysis of the intraven 514/242; 514/450; 514/653; 514/654 tricular fluid from parkinsonian patients”, Journal Of the (58) Field of Search ................................. 514/567, 653, Neurological Sciences, vol. 139, pp. 141-148, (1996). 514/217, 654, 211, 450, 242 Naoi et al., “L-Threo-3,4-Dihydroxyphenylserine (DOPS) Aldolase: A New Enzyme Cleaving DOPS Into Protocat (56) References Cited echualdehyde and Glycine”, Biochemical and Biophysical Research Communications, vol. 143, No. 2, pp. 482-488, U.S. PATENT DOCUMENTS (Mar. 1987). 3,723,514 A 3/1973 Hegedus et al. 4,480,109 A 10/1984 Ohashi et al. (List continued on next page.) 4,562.263 A 12/1985 Ohashi et al. 5,266,596 A 11/1993 Yokokawa et al. Primary Examiner William R. A. Jarvis 5,288.898 A 2/1994 Umezawa et al. (74) Attorney, Agent, or Firm-Fish & Richardson P.C. 5,739,387 A 4/1998 Oda et al. 5,864.041 A 1/1999 Oda et al. (57) ABSTRACT OTHER PUBLICATIONS Norepinephrine uptake 2 inhibitors (or their precursors) are administered to enhance the effect of norepinephrine Abstract from EP-112606-A (Jul. 1984). reuptake inhibitors and other antidepressants. The uptake 2 Abstract from J59199660 (Nov. 1984). inhibitor may be combined in a single medication with a Abstract from EP-528729-A+(Feb. 1993). norepinephrine reuptake inhibitor, Such as imipramine, Abstract from EP-576941-A+(Jan. 1994). desipramine, or reboxetine, in order to inhibit both uptake Bartholini et al., “The Stereoisomers of 3,4-Dihydroxyphe mechanisms. The norepinephrine uptake 2 inhibitors may nylserine as Precursors of Norepinephrine”, The Journal of also be combined with MAO inhibitors or with selective Pharmacology and Experimental Therapeutics, vol. 193, Serotonin reuptake inhibitors. Alternatively, the norepineph No. 3, pp. 523-532, (1974). rine uptake 2 inhibitors may be useful antidepressants in Bolden-Watson et al., “Blockade by Newly-Developed their own right, without the need for co-administration of Antidepressants of Biogenic Amine Uptake into Rat Brain other antidepressants. One class of norepinephrine uptake 2 Synaptosomes", Life Sciences, vol. 52, pp. 1023-1029, (Jan. inhibitors is normetanephrine (the O-methylated metabolite 1993). of norepinephrine) and normetanephrine precursors such as Creveling et al., “The Combined Use of a-Methyltryosine 3(4-hydroxy-3-methoxyphenyl)-serine (4H-3MePS ), par and Threo-Dihydroxyphenylserine-Selective Reduction of ticularly L-threo-3-(4-H-3 MePS) that are transported to the Dopamine Levels in the Central Nervous System”, Bio brain where they are converted into normetanephrine, chemical Pharmacology, vol. 17, pp. 65-70, Pergamon thereby enhancing the effect of other antidepressants. For Press, (1968). example, the invention enhances the antidepressant effect of Grundemann et al., “Molecular identification of the corti norepinephrine reuptake inhibitors. costerone-Sentsitive eXtraneuronal catecholamine trans porter', Nature Neuroscience, vol. 1, No. 5, (Sep. 1998). 32 Claims, 1 Drawing Sheet US 6,403,645 B2 Page 2 OTHER PUBLICATIONS Schildkraut et al., “Normetanephrine Excretion and Affec Porter et al., “(S)-Norepinephrine * in the Tissues of Mice tive State in Depressed Patients Treated with Imipramine”, and Rats Given Racemic Erythro-3, 4-Dihydroxyphe Amer. J. 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Maruyama et al, Clinical Neurology, No. 34,985–990, 1994. U.S. Patent Jun. 11, 2002 US 6,403,645 B2 " HO CH COOH d NH Sch 1. N-1 2 H2 NH2 -o- HO Decarboxylase HO OCH OCH 4-hydroxy-3-methoxyphenylserine Normetanephrine 4-H-3MePS Fig. 1 US 6,403,645 B2 1 2 ANTDEPRESSANT EFFECT OF norepinephrine and normetanephrine. However, by the NOREPINEPHRINE UPTAKE 2 INHIBITORS fourth week of treatment with desipramine, urinary levels of AND COMBINED MEDICATIONS norepinephrine and normetanephrine showed Statistically INCLUDING THEM Significant increases, and these increases were even more pronounced and Statistically significant after Six weeks of This application claims priority to provisional applica treatment with desipramine. Similar findings were observed in Studies of levels of norepinephrine in plasma during tion No. 60/189,828, filed Mar. 16, 2000. treatment with desipramine in these patients. (Plasma levels TECHNICAL FIELD of normetanephrine were not measured in these studies.) Without wishing to bind ourselves to a specific molecular This invention is in the general field of central nervous mechanism to the exclusion of other mechanisms, various System medications, particularly antidepressants. Substances Such as normetanephrine block uptake of nore pinephrine via uptake 2. Moreover, Such uptake 2 inhibitors BACKGROUND complement norepinephrine uptake 1 inhibitors, in that each Norepinephrine is released from presynaptic noradrener 15 Works independently to enhance extraneuronal norepineph gic neurons into the Synapse. One therapy for clinical rine levels in the brain. The invention therefore further depression is administration of drugs known as norepineph increases levels of norepinephrine present at the Synapse and rine reuptake inhibitors, Such as imipramine, desipramine, or Surrounding extraneuronal Spaces, thereby providing a more reboxetine, which inhibit the reuptake of norepinephrine rapid antidepressant effect for norepinephrine reuptake into the presynaptic neuron ("uptake 1), the main mecha inhibitors. nism of inactivating norepinephrine at the Synapse. Again, without wishing to bind ourselves exclusively to a Reuptake inhibition thus increases Synaptic norepinephrine mechanism of action, we note the following regarding the levels. Bolden-Watson and Richelson, Life Sciences, invention’s ability to reduce the time required for clinical 52:1023–1029 (1993), hereby incorporated by reference, antidepressant effects from the administration of norepi discloses a method for determining reuptake inhibition. 25 nephrine reuptake inhibitors. Reuptake inhibition at uptake Typically these drugs are administered chronically and there 1 Sites initially results in an increase of norepinephrine at the may be a significant delay, e.g. 4-6 weeks, between the onset Synapse. This results in the activation of presynaptic alpha of therapy and clinical improvement. adrenergic receptors as well as Somatodendritic alpha adrenergic receptors on noradrenergic neuronal cell bodies Other therapies feature the administration of other classes in the locus coeruleus (the nucleus containing norepineph of drugs, Such as monoamine oxidase (MAO) inhibitors or rine cell bodies in the brain), and the consequent feedback Selective Serotonin