Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-05-09
2001-12-11
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230200, C514S212010
Reexamination Certificate
active
06329368
ABSTRACT:
FIELD OF THE INVENTION
The field of this invention is modulation of mammalian endocrine systems.
BACKGROUND OF THE INVENTION
The mammalian endocrine system is critical to mammalian cell-cell communication. In the endocrine system, hormones are secreted by endocrine glands into the circulatory system and adsorbed onto specific receptors, usually located distal to the site of secretion. The endocrine system is used by mammals to orchestrate a variety of different physiological processes, including metabolism, growth and maturation, circadian cycles and the like.
An important member of the endocrine system is the hypothalamic-pituitary axis. In general, this member of the endocrine system has two components: 1) a magnocellular (large cell) system which releases the hormones oxytocin and vasopressin (arginine vasopressin, AVP) directly into the blood stream from axon terminals located in the posterior pituitary and 2) a parvocellular (small cell) system that secretes small peptides called releasing factors which enter fenestrated capillaries, descend through the hypophyseal portal veins, and then diffuse through additional fenestrated capillaries to individual cells of the anterior pituitary. Principal neuropeptides secreted by the hypothalamus include growth hormone releasing hormone (GHRH), growth hormone release-inhibiting hormone (somatostatin), prolactin release inhibitory factor (dopamine), gonadotropin-releasing hormone (GnRH), corticotropin-releasing hormone (CRH), and thyrotropin-releasing hormone (TRH). Hormones released by the pituitary in response to hypothalamus neuropeptide influence include growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH, corticotropin) and thyrotropin (thyroid stimulating hormone, TSH).
The magnocellular and parvocellular secretory regions of the hypothalamus receive strong inputs from a variety of regions including other segments of the hypothalamus, diverse areas of the brain stem, and from forebrain (telencephalic) structures. See FIG.
1
. Prominent in the last group are projections from the limbic system including the central and medial divisions of the amygdala and the closely related bed nucleus of the stria terminals.
Abnormalities in endocrine or hormonal systems, e.g. hypo- or hypersecretion of one or more particular hormones, can have a profound affect on the ability of a mammal to function. For example, hypersecretion of pituitary hormones can result in a number of different diseased states, including: Cushing's syndrome (ACTH), acromegaly and gigantism (GH), and the like. Hyposecretion of pituitary hormones is also implicated in a number of diseased states, including dwarfism (GH), Sheehan's syndrome (panhypopituitarism), and the like.
Recently, age dependent dysfunction of hormonal systems has been postulated to be associated with the mammalian aging process. For example, GH blood levels in the elderly are lower than GH blood levels in younger populations, where lower GH blood levels have been theorized to be associated with symptoms of the aging process, such as decreases in lean body mass, muscle and bone.
Current methods of treating diseases associated with endocrine system dysfunction involving the hyposecretion of one or more particular hormones have centered on direct hormonal replacement, e.g. synthetic or recombinant growth hormone for GH deficient youths. While such approaches can be successful, hormone replacement therapy can be associated with a number of different disadvantages, such as risk of pathogen transmission, delivery, over compensation of replacement hormone, and the like.
As such, there continues to be an interest in the development of new methods of treating diseases characterized by endocrine system dysfunction. Of particular interest is the identification of small molecules which have a modulatory effect in the amount of endogenous hormone production, and methods of using such molecules in the regulation of hormonal circulatory levels.
RELEVANT LITERATURE
References describing the presence and distribution of AMPA type glutamate receptors in the hypothalamus include: Aubry et al., (1996) “Expression of ionotropic receptor subunit mRNAs by paraventricular corticotropin-releasing factor (CRF) neurons,”
Neurosci. Lett.
205:95-98; Van den Pool et al. (1994) “Ionotropic glutamate receptor gene expression in the hypothalamus: Localization of AMPA, kainate and NMDA receptor mRNA with in situ hybridization,”
J. Comp. Neurology
343:428-444; Brann (1995) “Glutamate: a major excitatory transmitter in neuroendocrine regulation.
Neuroendocrinology
61:213-225; Ginsberg et al. (1995) “The AMPA glutamate receptor GluR3 is enriched in oxytocinergic magnocellular neurons and is localized at synapses,”
Neuroscience
65:564-575.
References describing the effects of AMPA receptor agonists on the excitation of hypothalamic neurons and on the release of releasing factors include: Nissen et al. (1995), “Regulation of spontaneous phasic firing of rat supraoptic vasopressin neurons in vivo by glutamate receptors,”
J. Physiol.
484:415-424; Donoso et al. (1990) “Glutamate receptors of the non-NMDA types mediate the increase in Luteinizing Hormone-Releasing Hormone release by excitatory amino acids,”
Endocrinology
126:414-420; Lopez et al. (1992) “Endogenous excitatory amino acids and glutamate receptor subtypes involved in the control of hypothalamic luteinizing hormone-releasing hormone secretion,”
Endocrinology
130:1986-1992; Parker and Crowley (1993) “Stimulation of oxytocin release in the lactating rat by central excitatory amino acid mechanisms: evidence for specific involvement of AMPA sensitive glutamate receptors,”
Endocrinology
133:2847-2854; Brann et al. (1993) “Role of non-NMDA receptor neurotransmission in steroid and preovulatory gonadotropin surge expression in the female rat,”
Mol. Cell. Neurosci.
4:292-297; Ping et al. (1994) “A physiological role for N-methyl-D-aspartic acid and non-N-methyl-D-aspartic acid receptors in pulsatile gonadotropin secretion in the adult female rat,”
Endocrinology
135:113-118.
References studying the influence of glutamate receptor agonists on gene expression of hypothalamic factors include: Gore and Roberts (1994) “Regulation of GnRH gene expression by the excitatory amino acids kainic acid and NMDA in the male rat,”
Endocrinology
134:2026-2031. References describing age associated changes in the production of pituitary hormones include: Crew et al. (1987) “Age-related decrease of growth hormone production and prolactin gene expression in the mouse pituitary,”
Endocrinology
121:1251-1255; Martinoli et al. (1991) “Growth hormone and somatostatin gene expression in adult and aging rats as measured by quantitative in situ hybridization,”
Neuroendocrinology
57:607-615.
SUMMARY OF THE INVENTION
Methods for modulating mammalian endocrine systems are provided. In the subject methods, allosteric modulators of AMPA receptors of the hypothalamus, e.g. agents belonging to the “ampakine” family of compounds, are administered to the host. The subject methods find use in a variety of different applications where modulation of the endocrine system of a mammal is desired, such as in the treatment of diseases associated with hormonal system dysfunction, particularly with abnormally decreased circulatory levels of a hormone, e.g. growth hormone, resulting from down regulation in endogenous hormonal production.
It is an object of the invention to treat hormonal imbalances. Another object of the invention is to show the effects of aging related to decreases in hormonal levels which normally occur with aging.
An advantage of the invention is that a host's endogenous hormones are used.
A feature of the invention is that formulations with specific positive modulators of AMPA type glutamate receptors are employed.
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the subject invention, as mo
Lynch Gary
Van Der Klish Peter
Borden Paula A.
Bozicevic Field & Francis LLP
Field Bret
The Regents of the University of California
Weber Jon P.
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