Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-24
2004-06-08
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S288000
Reexamination Certificate
active
06747060
ABSTRACT:
The present invention relates to non-natural galanin receptor ligands which can function as agonists and antagonists of galanin and can be used to treat diseases or conditions in which galanin plays a role.
BACKGROUND OF THE INVENTION
Galanin
1
is a 29/30 amino acid long neuroendocrine peptide that potently affects seizure activity, cognition, mood, feeding, and pain threshold
2-6
. Galanin-overexpressing mice have increased resistance to status epilepticus, while galanin knockout mice have lowered seizure threshold
6
. These results indicate that endogenous galanin is an important determinant of hippocampal excitability and of seizure threshold. The importance of galanin agonists for seizure control may arise from their ability to act at both pre- and postsynaptic sites to reduce excitability, to inhibit glutamate but not GABA release
7
, and to hyperpolarize both dentate granule cells and CA1-CA3 pyramidal cells by opening K+-channels
8
, dampening seizure activity. Although intracerebroventricularly injected galanin blocks seizures
5
in mice, this large peptide is unable to cross the blood-brain barrier and is rapidly degraded.
To date, there are only two reports on non-peptide ligands for galanin receptors, which behave as antagonists: spirocoumaranon
9
(Sch 202596; IC50 of 1.4 &mgr;M at human GalR1) and dithiipin-1,1,4,4-tetroxide
10
(IC50 of 0.17 &mgr;M at human GalR1), despite extensive random screening efforts at six large pharmaceutical companies.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided low molecular weight ligands for galanin receptor(s) having the formula:
wherein:
R
1
, R
1
′, and R
1
″ are each independently hydrogen or lower alkyl,
R
2
and R
2
′ are each independently an optionally substituted hydrocarbyl moiety containing at least about four carbon atoms,
E is optional, and, if present, is O, N or S,
X is a hydrocarbyl moiety bearing at least one substituent, wherein at least one of said substituents bears a positive charge,
Ar is an optionally substituted aromatic or heteroaromatic moiety having at least about three carbon atoms, and
n is 1, 2 or 3.
A preferred embodiment of the above compounds has been given the name “galnon”: Fmoc-Cha-Lys-amidomethyl coumarin (according to IUPAC systematic nomenclature: 1-[5-amino-1-(4-methyl-2-oxo-2H-chromen-7-ylcarbamoyl)-pentylcarbamoyl]-2-cyclohexyl-ethyl-carbamic acid 9H-fluoren-9-ylmethyl ester).
The galanin receptor ligands of the invention are characterized in having galanin agonist or antagonist activity, are generally 700 daltons or less in molecular weight, and have the ability to cross the blood-brain barrier.
Also provided herein are various uses for the invention ligands, including in vitro and in vivo analysis of galanin receptor structure and function, and use in treating a variety of diseases and conditions in which galanin plays a role. Such diseases or conditions include convulsions such as in epilepsy, growth, diabetes, pain, allodynia psychiatric states, cognition, and feeding. For such uses, the invention compounds can be formulated with an appropriate excipient(s) for pharmaceutical administration to a mammalian patient.
These and other aspects of the invention will be addressed in greater detail below.
REFERENCES:
Saar, K et al, ‘Anticonvulsant activity of a nonpeptide galanin receptor agonist’ Proceedings of the National Academy of Sciences of the United States of America (2002), 99(10), 7136-7141.*
Salvati, Luca et al, ‘Modulation of the catalytic activity of cruzipain, the major cysteineproteinase fromTrypanosoma cruzi, by temperature and pH’ European Journal of Biochemistry (2001), 268(11), 3253-3258.*
McKie, J. H., ‘Specific peptide inhibitors of trypanothione reductase with backbonestructures unrelated to that of substrate: potential rational drug design lead frameworks’ Amino Acids (2001), 20(2), 145-153, CA 135:204909.*
Bartfai and Langel, “Galanin receptor ligands as potential therapeutic agents in depression and neurodegeneration.” Eur. J. Med. Chem., 30: S163-S174, 1995.
Bartfai, T., “Galanin: A neuropeptide with important central nervous system actions” in Psychopharmacology: The Fourth Generation of Progress, edited by Bloom and Kupfer, New York: Raven Press, 1995, p. 563-571.
Chu, et al., “A new fungal metabolite, Sch 202596, with inhibitory activity in the galanin receptor GALR1 assay.” Tetrahedron Letter, 38: 6111-6114, 1997.
Land et al., “Linear and cyclic N-terminal galanin fragments and analogs as ligands at the hypothalamic galanic receptor.” Int. J. Peptide Protein Res., 38: 267-272, 1991.
Land et al., “Assay for galanin receptor.” In Methods in Neurosciences, edited by P.Michael Conn, San Diego: Academic Press, vol. 5: 225-234, 1991.
Langel and Bartfai, “Chemistry and molecular biology of galanin receptor ligands.” Ann. NY Acad. Sci., 863: 86-93, 1998.
Mazarati et al., “Anticonvulsant activity of the first systemically active galanin receptor agonist.” Abstracts Scoiety for Neuroscience, 31stannual meeting, San Diego, CA., Nov. 10-15, 2001, 27: 2005.
Mazarati et al., “Anticonvulsive effects of galanin administered into the central newvous system upon the picrotoxin-kindled seizure syndrome in rats.” Brain Research, 589:164-166, 1992.
Mazarati et al., “Galatin modulation of seizures and seizure modulation of hippocampal galanin in an animal model of status epilepticus.” J.Neuroscience, 18:10070-10077, 1998.
Mazarati et al., “Modulation of hippocampal excitability and seizures by galanin.” J. Neuroscience, 20: 6276-6281, 2000.
Pooga et al., “Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo.” Nature Biotechnology, 16: 857-861, 1998.
Scott et al., “2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor.” Bioorg. Med. Chem., 8: 1383-1391, 2000.
Tatemoto et al., “Galanin-a novel biologically active peptide from porcine intestine.” FEBS Letters, 164: 124-128, 1983.
Valkna, et al., “Effects of chimeric galanin receptor ligands on basal adenylate cyclase activity in rat ventral hippocampal membranes.” Protein Peptide Letters, 2: 267-274, 1995.
Valkna et al., “Differential regulation of adenylate cyclase activity in rat ventral and dorsal hippocampus by rat galanin.” Neuroscience Letters, 187: 75-78, 1995.
Xu et al., “Electrophysiological evidence for a hyperpolarizing galanin (1-15)- selective receptor on hippocampal CA3 pyramidal neurons.” Proc. Nat. Acad. Sci. USA, 96: 14583-7, 1999.
Young and Kuhar, “A new method for receptor autoradiography: [3H]opioid receptors in rat brain.” Brian Research, 179: 255-270, 1979.
Zini et al., “Galanin reduces release of endogenous excitatory amino acids in the rat hippocampus.” Eur. J. Pharmacol. Molec. Pharm., 245: 1-7, 1993.
Cain et al., “Production, Purification, and Characterization of Recombinant Prohormone Convertase 5 from Baculovirus-Infected Insect Cells.” Protein Expression and Purification, 24: 227-233, 2002.
Floren et al., “Galanin receptor subtypes and ligand binding.” Neuropeptides, 34(6): 331-337, 2000.
STN International, file ZCAPLUS, ZCAPLUS accession No. 2001:9514, Document No. 134:189890. Abe et al., “Design and synthesis of sensitive fluorogenic substrates specific for Lys-gingipain.” Journal of Biochemistry (Tokyo) 128(5): 877-881, 2000. Abstract.
STN International, file ZCAPLUS, ZCAPLUS accession No. 1980:193362, Document No. 92:193362. Iwanaga et al., “Fluorogenic peptide substrates for proteases in blood coagulation, kallikrein-kinin and fibrinolysis systems.” Adv. Exp. Med. Biol. (1979), Volume Date 1978, 120A(Kinins 2: Biochem., Pathophysiol., Clin. Aspects) 147-163. Abstract.
International Search Report for PCT Application No. PCT/SE02/01002.
Bartfai Tamas
Hallnemo Gerd
Hellberg Sven
Langel Ulo
Saar Kulliki
Foley & Lardner
Kemia, Inc.
Owens Amelia
Warburg Richard J.
LandOfFree
Non-natural galanin receptor ligands does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Non-natural galanin receptor ligands, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Non-natural galanin receptor ligands will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3335761