Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-28
2004-05-11
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S422000, C514S423000, C514S475000, C514S613000, C514S616000, C514S617000, C514S619000, C514S620000, C514S621000, C514S622000, C514S625000, C514S626000, C514S627000, C514S702000, C514S703000, C514S704000, C514S705000
Reexamination Certificate
active
06734204
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the use of oleamide based analogs that potentiate serotonin receptor subtypes. Some of the analogs are more potent agonists than oleamide and some of the analogs possess dual agonist/antagonist activity. Such analogs may permit selective modulation of or even have opposing effects on different serotonin receptor subtypes.
BACKGROUND
Oleamide (1) is an endogenous fatty acid primary amide that accumulates in the cerebrospinal fluid under conditions of sleep deprivation and induces physiological sleep in animals (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). 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 (Patterson et al. (1996)
J. Am. Chem. Soc
. 118, 5938-5945; Cravatt et al. (1996)
Nature
384, 83-87; Giang et al.
Proc. Natl. Acad. Sci. USA
94, 2238-2242; Thomas et al. (1997)
J. Neuroscience Res
. 50, 1-6; Merkler et al. (1996)
Arch. Biochem. Biophys
. 330, 430-434).
Fatty acid amide hydrolase (FAAH) is an integral membrane protein that degrades 1 to oleic acid and potent inhibitors of the enzyme have been detailed (Koutek et al. (1994)
J. Biol. Chem
. 269, 22937-22940; Petrocellis et al. (1997)
Biochem. Biophys. Rsch. Commun
. 231, 82-88; Deutsch et al. (1997)
Biochem. Pharmacol
. 53, 255-260). The characterization and neuronal distribution of FAAH have been disclosed and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide which serves as an endogenous ligand for the cannabinoid receptor (Devane et al. (1992)
Science
258, 1946-1949; Di Marzo et al. (1995)
Prostaglandins, Leukot. Essent. Fatty Acids
53, 1-11). Unlike anandamide, an appealing feature 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 peptide hormones terminating in a primary amide.
Recent studies have shown the oleamide modulates serotonergic neurotransmission (Huidobro-Toro et al. (1996)
Proc. Natl. Acad. Sci. USA
93, 8078-8082; Thomas et al. (1997)
Proc. Natl. Acad. Sci. USA
94, 14115-14119). In the first disclosure of such effects, oleamide was shown to potentiate 5-HT
2C
and 5-HT
2A
receptor-mediated chloride currents in transfected frog oocytes, but not those elicited by the 5-HT
3
ion-gated channel receptor or other G protein coupled receptors. This potentiation was greatest for the 5-HT
2C
receptor subtype where the effect was observed at concentrations as low as 1 nM and was maximal at 100 nM oleamide. Oleamide did not alter the serotonin (5-HT) EC
50
but instead increased receptor efficacy.
Similarly, oleamide has been reported to potentiate phosphoinositide hydrolysis in rat pituitary P11 cells expressing the 5-HT
2
receptor but to inhibit 5-HT
7
receptor-mediated stimulation of cAMP levels in HeLa cells transfected with the receptor. In these efforts, oleamide was shown to act as a weak agonist at the 5-HT
7
receptor but to behave as an unsurmountable antagonist in the presence of serotonin illustrating that it may act at an allosteric site (Huidobro-Toro et al. (1996)
Proc. Natl. Acad. Sci. USA
93, 8078-8082; Thomas et al. (1997)
Proc. Natl. Acad. Sci. USA
94, 14115-14119). Thus, oleamide has been shown to enhance (5-HT
2A
, 5-HT
2C
), disrupt (5-HT
7
), or have no effect (5-HT
3
) on serotonergic signal transduction at various receptor subtypes. Serotonin receptors have been implicated in anxiety, depression, appetite, thermoregulation as well as sleep and mood regulation and strong links between 5-HT
1
, 5-HT
2
, and 5-HT
7
, and the regulation of sleep have been disclosed (Leonard et al. (1996)
Psychother. Psychosom
. 65, 66-75; Lovenberg et al. (1993)
Neuron
11, 449-458).
What is needed are analogs which possess inhanced activity and selectivity over that of oleamide for the potentiation of serotonergic signal transduction at various receptor subtypes.
SUMMARY OF THE INVENTION
The invention is directed to the use of analogs which potentiate serotonin receptor subtypes. Many of the analogs are more potent agonists than oleamide and some of the analogs possess dual agonist/antagonist activity. Such analogs may permit selective modulation of or even have opposing effects on different serotonin receptor subtypes.
One aspect of the invention is directed to a method for selectively potentiating a cell having a serotonin receptor subtype 5-HT
1A
. The method employs the step of contacting the cell having the serotonin receptor subtype 5-HT
1A
with a quantity of serotonergic agent possessing 5-HT
1A
agonist activity sufficient for potentiating said cell. Preferred serotonergic agents include compounds represented by the structure:
In the above structure, X is a diradical selected from the group represented by the following structures:
In the above structures, Z is a radical selected from the group consisting of: —CH
2
and O; Y is a diradical selected from the group consisting of: —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)—, and —CH
2
N(CH
3
)C(═O)—; R
1
is a radical selected from the group consisting of: 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
)3NH—, 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—, HOCH
2
CH(OAc)CH
2
O—, and HO
2
CCH
2
NH—; R
2
is a radical selected from the group consisting of: —CH
3
, —CH
2
OCH
3
, and —CO
2
H; and 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.
Another aspect of the invention is directed to a method for selectively enhancing a serotonergic signal transduction response of a cell having serotonin receptor subtype 5-HT
1A
. Enhancement is achieved by contacting the cell, in the presence of serotonin, with a quantity of the above serotonergic agent possessing 5-HT
1A
agonist activity sufficient to selectively enhance the serotonergic signal transduction response of said cell.
Another aspect of the invention is directed to a method for selectively potentiating a cell having a serotonin receptor subtype 5-HT
2A
. The method employs the step of contacting the cell having the serotonin receptor subtype 5-HT
1A
with a quantity of a serotonergic agent possessing 5-HT
2A
agonist activity sufficient to selectively potentiate such cell. Preferred serotonergic agents include compounds represented by the structure:
In the above structure, X is a diradical selected from the group represented by the following structures:
In the above structures, Z is —CH
2
—; Y is a diradical selected from the group consisting of: —CH
2
—, —CH(CH
3
)—, —O—, —CHCl—, —CH
2
NHC(═O)—, and —CH
2
N(CH
3
)C(═O)—; R
1
is a radical selected from the group consisting of: hydrogen, —NH
2
, OH, MeNH—, Me
2
N—, EtNH—, Et
2
N—, CH
2
═CHCH
2
NH—, HONH—, MeONMe-, NH
2
NH—, CF
3
—, and ClCH
2
—; R
2
is a radical selected from the group consisting of: —CH
3
and —CH
2
OH; and 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, the following provisos apply: if Y is CH
2
, X is an ethene diradical, R
1
is —NH
2
, and R
2
is —CH
3
, then n cannot be 1 if m is 12; n cannot be 2 if m is 9; n cannot be 4 if m is 9; n cannot be 5 if m is 2, 4, 6, 8, 10 and 12; n cannot be 6 if m is 6; n cannot be 7 if m is 6; and n cannot be 8 if m is 3.
Another aspect of the invention is directed to a method for selectively enhancing a serotonergic si
Krass Frederick
Lewis Donald G.
The Scripps Research Institute
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