Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-19
2001-06-26
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S422000, C514S423000, C514S613000, C514S702000, C514S703000, C514S705000, C554S051000, C554S055000, C554S056000, C554S059000, C554S213000, C554S214000, C554S223000, C548S400000, C548S514000, C548S530000
Reexamination Certificate
active
06251931
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds that serve both as oleamide agonists and as inhibitors of fatty acid amide hydrolase. More particularly, the present invention relates to oleamide agonists for inhibition of gap junction-mediated chemical and electrical transmission in glial cells.
BACKGROUND
Oleamide (1) is an endogenous fatty acid primary amide shown to accumulate in the cerebrospinal fluid under conditions of sleep deprivation and disappear upon sleep recovery (Cravatt et al. (1995)
Science
268, 1506-1509; Lerner et al. (1994)
Proc. Natl. Acad. Sci. USA
91, 9505-9508; Cravatt et al. (1996)
J. Am. Chem. Soc.
118, 580-590). In a structurally specific manner, it has been shown to induce physiological sleep in animals when administered by ip or iv injection. Consistent with its role as a prototypical member of a new class of biological signaling molecules, enzymatic regulation of the endogenous concentrations of oleamide has been described or proposed.
Fatty acid amide hydrolase (FAAH, oleamide hydrolase) is an integral membrane protein that degrades 1 to oleic acid and potent inhibitors (Ki=13 &mgr;M
−1
nM) of the enzyme with sleep-inducing properties have been detailed. The purification, characterization, cloning, expression and neuronal distribution of FAAH have been disclosed and it was found to possess the capabilities of hydrolyzing a range of fatty acid amides including anandamide which serves as an endogenous ligand for cannabinoid receptors.
In contrast to anandamide, an appealing feature of the members of this new class of biological signaling agents is the primary amide suggesting that their storage and release may be controlled in a manner analogous to that of short peptide hormones and messengers terminating in a primary amide (Patterson et al. (1996)
J. Am. Chem. Soc.
118, 5938-5945; Cravatt et al. (1996)
Nature
384, 83-87; Giang et al. (1997)
Proc. Natl. Acad. Sci. USA
94, 2238-2242; Merkler et al. (1996)
Arch. Biochem. Biophys.
330, 430-434; Devane et al. (1992)
Science
258, 1946-1949; Johnson et al. (1993)
Protaglandins, Leukot. Essent. Fatty Acids
48, 429-437; Di Marzo et al. (1995)
Prostaglandins, Leukot. Essent. Fatty Acids
53, 1-11).
SUMMARY OF THE INVENTION
The invention is directed to inhibitors of gap junction communication. More particularly, one aspect of the invention is directed to compounds having oleamide agonist activity for inhibiting gap junction-mediated chemical and electrical transmission in glial cells. Preferred compounds are represented by the structure:
In the above structure, X is one of the diradicals represented by the following structures:
wherein Z is either —CH or O. Y is a diradical selected from the the following: —CH
2
—, —CH(CH
3
)—, —C(CH
3
)
2
—, —O—, —NH—, —CH(SH)—, —CHSAc)—, —CH(OH)—, —CHCl—, —C(═O)—, —C(═O)CH
2
—, —CH
2
NHC(═O)—, or —CH
2
N(CH
3
)C(═O)—. R
1
is a radical selected from the following: hydrogen, —NH
2
, OH, MeNH—, Me
2
N—, EtNH—, Et
2
N—, CH
2
═CHCH
2
NH—, n-propyl-NH—, i-propyl-NH—, cyclopropyl-NH—, i-propyl-NMe—, butyl-NH—, pyrrolidine-, phenyl-NH—, phenyl(CH
2
)
3
NH—, HONH—, MeONMe—, NH
2
NH—, CH
3
O—, CH
3
CH
2
O—, CH
3
(CH
2
)
2
O—, Me
2
CHCH
2
O—, H—, CF
3
—, BrCH
2
—, ClCH
2
—, N
2
CH—, HOCH
2
CH
2
NH—, (HOCH
2
CH
2
)
2
N—, HOCH
2
CH
2
CH
2
NH—, or HOCH
2
CH(OAc)CH
2
O—. R
2
is a radical selected from the following:
—CH
3
, —(CH
2
)
2
CH
3
, —(CH
2
)
4
CH
3
, —(CH
2
)
6
CH
3
, —CH
2
OCH
3
, —CH
2
OH, —CONH
2
or —CO
2
H. n is an integer from 0 to 15; m is an integer from 0 to 15 with the requirement that the sum of n+m is an integer from 11 to 15. However, if Y is CH
2
, n is 4, m is 7, and R
2
is CH
3
, then R
1
cannot be a radical selected from the group consisting of —CF
3
and hydrogen. Furthermore, if Y is CH
2
, n is 5, m is 7, and R
2
is CH
3
, then R
1
cannot be a radical selected from the group consisting of —CF
3
, —CH
2
Cl, —NHOH, —C(O)NH
2
, —CN
2
, and —C(O)OEt. If Y is CHCl, n is 4, m is 7, and R
2
is CH
3
, then R
1
cannot be NH
2
. If Y is CH(OH), n is 4, m is 7, and R
2
is CH
3
, then R
1
cannot be NH
2
. If Y is C(═O), n is 4, m is 7, and R
2
is CH
3
, then R
1
cannot be NH
2
and CH
3
CH
2
O—. And finally, if Y is CH
2
, 4≦n≦9, 4≦n≦7, and R
2
is CH
3
, then R
1
cannot be NH
2
and OH.
Another aspect of the invention is directed to a method for inhibiting gap junction mediated chemical and electrical transmission in glial cells by contacting such cells with the oleamide agonists represented above.
REFERENCES:
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Aylsworth, et al., “Influence of Lipids on Gap-Junction-mediated Intercellular Communication between Chinese Hamster Cells in Vitro”,Cancer Res. 46: 4527-4533 (1996).
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Schmid, et al., “N-Acylated Glycerophospholipids and Their Derivatives”,Prog. Lipid Res. 29: 1-43 (1990).
Wakamatsu, et al., “Isolation of Fatty Acid Amide as an Angiogenic Principle from Bovine Mesentery”,Biochem. Biophys. Res. Commun. 168: 423-429 (1990).
Spray, et al., “Structure-Activity Relations of the Cardiac Gap Junction Channel”,Am. J. Physiol. 258: C195-C205 (1990).
Burt, et al., “Uncoupling of Cardiac Cells by Fatty Acids: Structure-Activity Relationships”,Am. J. Physiol. 260: C439-C448 (1991).
Hasler, et al., “Inhibition of Gap Junction-Mediated Intercellular Communication by &agr;-Linolenate”,Am. J. Physiol. 261: C161-C168 (1991).
Ramachandran, et al., “Enzymatic Hydrolysis of Sphingomyelin in 3T3-Li Cells: Modulation by Dexamethasone”,Biochem. Arch. 8: 369-377 (1992).
Massey, et al., “Arachidonic Acid and Lipoxygenase Metabolites Uncouple Neonatal Rat Cardiac Myocyte Pairs”,Am. J. Physiol. 263: C494-C501 (1992).
Jain, et al., “Fatty Acid Amides: Scooting Mode-Based Discovery of Tight-Binding Competitive Inhibitors of Secreted Phospholipases A2”,J. Med. Chem. 35: 3584-3586 (1992).
Felder, et al., “Anandamide, an Endogenous Cannabimimetic Eicosanoid, Binds to the Cloned Human Cannabinoid Receptor and Stimulates Receptor-Mediated Signal Transduction”,Proc. Natl. Acad. Sci. USA 90: 7656-7660 (1993).
Hirschi, et al., “Oleic Acid Differentially Affects Gap Junction-Mediated Communication in Heart and Vascular Smooth Muscle Cells”,Am. J. Physiol. 265: C1517-C1526 (1993).
Hanu{haeck over (s)}, et al., “Two New Unsaturated Fatty Acid Ethanolamides in Brain That Bind to the Cannabinoid Receptor”,J. Med. Chem. 36: 3032-3034 (1993).
Abadji, et al., “(R)-Methanandamide: A Chiral Novel Anandamide Possessing Higher Potency and Metabolic Stability”,J. Med. Chem. 37: 1889-1893 (1994).
Pinto, et al., “Cannabinoid Receptor Binding and Agonist Activity of Amides and Esters of Arachidonic Acid”,Mol. Pharmacol. 46: 516-522 (1994).
Adams, et al., “Pharmacological and Behavioral Evaluation of Aklylated Anandamide Analogs”,Life Sci. 56: 2041-2048 (1995).
Mechoulam, et al., “Identification of an Endogenous 2-Monoglyceride, Present in Canine Gut, that Binds to Cannabinoid Receptors”,Biochem. Pharmacol. 50: 83-90 (1995).
Priller, et al., “Mead Ethanolamide, a Novel Eicosanoid, Is an Agonist for the Central (CB1) and Peripheral (CB2) Cannabinoid Receptors”,Mol. Pharmacol. 48: 288-292 (1995).
Adams, et al., “Evaluation of Cannabinoid Receptor Binding and in Vivo Activities for Anandamide Amalogs”,J. Pharmacol. Exp. Ther. 273: 1172-1181 (1995).
Venance, et al., “Inhibition by Anandamide of Gap Junctions and Intercellular Calcium Signalling in Striatal Astrocytes”,Nature 376: 590-594 (1995).
Huidobro-Toro, et al., “Brain Lipids that Induce Sleep are Novel Modulators of 5-Hydroxytryptamine Receptors”,Proc. Natl. Acad. Sci. USA 93: 8078-8082 (1996).
Khanolkar, et al., “Head Group Analogs of Arachidonylethanolamide, the Endogenous Cannabinoid Ligand”,J. Med. Chem. 39: 4515-4519 (1996).
Boger Dale L.
Cravatt Benjamin F.
Gilula Norton B.
Lerner Richard A.
Carr Deborah D.
Northrup Thomas E.
The Scripps Research Institute
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