Chemistry: molecular biology and microbiology – Spore forming or isolating process
Patent
1994-08-22
1997-06-17
Walsh, Stephen
Chemistry: molecular biology and microbiology
Spore forming or isolating process
4353201, 935 9, 935 70, 536 235, 536 2431, C07H 2104, C12N 510
Patent
active
056396520
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced by partial citations within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.
Since the purification of a pressor substance in blood serum termed serotonin (Rapport et al., 1947) and later identified as 5-hydroxytryptamine (5-HT)(Rapport, 1949), there has been a plethora of reports demonstrating that this indoleamine not only plays a role in the functioning of peripheral tissues but, indeed, performs a key role in the brain as a neurotransmitter. Certainly, the anatomical localization of serotonin and serotonergic neurons in both the peripheral and central nervous systems supports its role in such diverse physiologic and behavioral functions as pain perception, sleep, aggression, sexual activity, hormone secretion, thermoregulation, motor activity, cardiovascular function, food intake and renal regulation (For review see Green, 1985; Osborne and Hamon, 1988; Sanders-Bush, 1988; Peroutka, 1991). Taken together, it appears that serotonin plays an important role in homeostasis and in modulating responsiveness to environmental stimuli. Accordingly, studies demonstrating that abnormalities in the serotonergic system may be associated with disease states has created a drug development effort towards agents which may selectively modulate the function oft serotonin (Glennon, 1990).
In relation to the characterization of physiologic or biochemical responses resulting from the release of serotonin are simultaneous investigations examining the receptor sites responsible for the actions elicited by the indoleamine transmitter. Following early in vitro pharmacological assays describing the existence of two different serotonin receptors, designated as D and M, in the guinea pig ileum (Gaddum and Picarelli, 1957), the advent of receptor binding technique in the 1970's has brought to light during the last decade the diversity of 5-HT receptors existing in both the brain and peripheral tissues. Thus, although the concept of D and M receptors has not been invalidated, serotonin receptors not fitting either category have been identified using radioligand methods. To date using this technique, there appears to be four classes of serotonin receptors found in the brain: 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3 and, putatively, 5-HT.sub.4 (Peroutka, 1991). Furthermore, 5-HT.sub.1 sites have been subclassified as: 5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1C, 5-HT.sub.1D (Hamon et al., 1990) and 5-HT.sub.1 E (Leonhardt et al., 1989). Although a detailed characterization of the 5-HT.sub.1 F binding site is lacking, extensive pharmacologic, biochemical and functional properties have clearly shown that the other four subtypes of 5-HT.sub.1 sites are receptors according to classical criteria.
During the last few years, the field of molecular biology has provided an important facet to receptor research by cloning these proteins and allowing more precise characterizations in isolated systems (Hartig et al, 1990). This has been accomplished for the 5-HT.sub.1A (Fargin et al., 1988), 5-HT.sub.1C (Julius et al., 1988), 5-HT.sub.1D (Branchek et al., 1990) and 5-HT.sub.2 receptors (Pritchett et al., 1988). Thus, there is no doubt that these binding sites represent "true" functional receptors. Indeed, the pharmacological characterization of serotonin receptors involved in various physiological or biochemical functions is a key component of drug development for the serotonergic system. As one can deduce from the diversity of serotonin binding sites, many targets are available for advancement in selective drug design. The coupling of molecular biological methods to pharmacological characterization particularly for cloned human receptors will open new avenues for pharmaceutical development which has not been previously explored.
This study is a pharmacological characterization of a serotonergic receptor
REFERENCES:
patent: 5360735 (1994-11-01), Weinshank et al.
Zgombick, J.M. et al., Mol. Pharmacol., 42:180-185, 1992.
Hamblin, M.W. et al., Molecular Pharmacology, 40:143-148, 1991.
Levy, F.O. et al., FEBS Letters, 296(2): 117-236, 1992.
McCallister, G. et al., PNAS, 89: 5517-5521, 1992.
Foguet, M. et al., Neuroreport, 3(4): 345-348, 1992.
Adham, N., et al. Proc. Natl. Acad. Sci. U.S.A. 1993; 90:408-412 (Exhibit D).
Amlaiky, N., et al. J. Biol. Chem. 1992; 267(28):19761-19664 (Exhibit E).
Leonhardt, S., et al. J. Neurochemistry 1989; 53:(2):465-471 (Exhibit F).
Branchek Theresa
Hartig Paul R.
Weinshank Richard L.
Spector Lorraine M.
Synaptic Pharmaceutical Corporation
Walsh Stephen
White John P.
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