Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-01-05
2001-05-29
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06239122
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSERED RESEARCH OR DEVELOPMENT
Not applicable.
REFERENCE TO A MICROFICHE APPENDIX
Not applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
A new use for estrone, derivatives of estrone, equilin and equilenin, including pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds is claimed.
2. Description of Related Art
Basic Science Prior Art
The 5-HT
3
receptor is a ligand-gated ion channel
The 5-hydroxytryptamine type 3 receptor (5-HT
3
receptor) is a member of the ligand-gated ion channel superfamily of proteins (Jackson, M. B. & Yakel, J. L., 1995, Ann. Rev. Physiol. 57:447-468). Ligand-gated ion channels are transmembrane proteins. They appear to be composed of five subunits assembled around a central channel that forms a pathway for ions. Binding of an agonist leads to the opening of the gate of the ion channel to allow movement of ions across the cell membrane. The natural agonist is serotonin (5-hydroxytryptamine, 5-HT). Two subunits of the 5-HT
3
receptor have been cloned to date (Maricq, A. V., Peterson, A. S., Brake, F. J., Myers, R. M. & Julius, D., 1991, Science, 254:432-437; Davies, P. A., Pistis, M., Hanna, M. C., Peters, J. A., Lambert, J. J., Hales, T. G. & Kirkness, E. F., 1999, Nature 397:359-363). Several immortal cell lines express high densities of 5-HT
3
receptors including the cell line that I used in my experiments (NCB-20). The cDNA cloned from the NCB-20 cell line is nearly identical (98% identity) to the cDNA cloned from humans (Maricq et al., 1991).
Steroids act on ligand-gated ion channels
The importance of steroids as crucial components of cellular membranes is well established. Equally well established are the long term endocrine effects of steroid hormones. These endocrine effects result from the binding of steroids to intracellular receptors that subsequently interact with DNA and modulate gene expression. Less well delineated, but currently the subject of increasing interest, are the immediate modulatory effects of certain steroids on ligand-gated ion channels (Rupprecht, R. & Holsboer, F., 1999, TINS 22(9):410-416). For example, it is now established that steroid anesthetics, as well as certain endogenous metabolic products of progesterone and deoxycorticosterone, act on the gamma-aminobutyric acid type A receptor (GABA
A
receptor) at extremely low concentrations. The GABA
A
receptor belongs to the same family of proteins as the 5-HT
3
receptor. However, most of the reported effects of steroids on ligand-gated ion channels occur at high micromolar concentrations and it is not clear that these effects have any physiological relevance or hold any potential for a therapeutic action. These nonspecific effects may result from the lipophilic nature of steroids. Although steroids have long been used as therapeutic agents for endocrine indications, no steroid is currently on the market as an agent that targets a ligand-gated ion channel. Alphaxalone, a steroid anesthetic that targeted the GABA
A
receptor, is the only example and it was withdrawn from the market because of problems with the pharmaceutical carrier.
Estrogens are steroids
Estrogens belong to a class of steroids that are responsible for the development of female secondary sexual characteristics as well as the differentiation, growth and functioning of many tissues in the male. Estrogens also play an important role in the establishment and maintenance of pregnancy. The three most abundant estrogens in humans are estradiol, estrone and estriol. Of the these three, estradiol is the most potent and is the major secretory product of the ovary. Estrogens are extensively metabolized. For example, estradiol administered orally to humans is metabolized to estrone by the gastrointestinal mucosa and the liver (Lievertz, R. W., 1987, Am. J. Obstet. Gynecol. 156:1289-1293). During pregnancy, estrogens are synthesized by the placenta in large quantities (De Hertogh, R. et al., 1975, J. Clin. Endocrinol. Metab. 40:93-101).
Estradiol is an antagonist of the 5-HT
3
receptor at high concentrations
I have found that estradiol antagonizes the 5-HT
3
receptor at high concentrations. The concentration of estradiol needed to inhibit the functioning of the 5-HT
3
receptor by 50% (IC
50
) was about 3 &mgr;M. This observation was presented in 1994 at the International Union of Pharmacologists (IUPHAR) meeting. This observation has also been published by another group (Wetzel, C. H. R., et al., 1998, Mol. Endocrinol. 12(9):1441-1451). Unfortunately, because such high concentrations of estradiol were needed to cause an effect, the action on the 5-HT
3
receptor is not of any physiological relevance. Normally, the plasma concentrations of estrogens are in the picomolar range. Only during the condition of pregnancy does the plasma level of estrogens rise into the low nanomolar range (De Hertogh, et al., 1975). This low affinity binding site for estradiol on the 5-HT
3
receptor is also not useful as a therapeutic target since unreasonably high concentrations of estradiol would have to be administered to a human to exert an effect on the 5-HT
3
receptor.
The presence of a low affinity binding site on the 5-HT
3
receptor for a steroid is predictable from the prior art because many different ligand-gated ion channels as well as G-protein coupled receptors have low affinity binding sites for steroids (Rupprecht & Holsboer, 1999). Since only a few high affinity binding sites have been found, it is not necessarily predictable that the 5-HT
3
receptor would have a high affinity binding site. More importantly, it is certainly not possible to predict the identity of a steroid which would have a high affinity for a receptor. This is because the existence of a high affinity binding site must first be established and then the structure-activity properties of the binding site must be elucidated. As detailed later in this specification, I surprisingly discovered a high affinity binding site on the 5-HT
3
receptor for estrone. This site is potentially useful as a therapeutic target for the treatment of nausea and/or vomiting and perhaps other, as yet unidentified therapeutic indications. The reason that this site is of potential therapeutic value is that only very low amounts of an estrogen would need to be administered to a human to acheive a therapeutic effect through an action on the 5-HT
3
receptor.
The 5-HT
3
receptor is involved in the control of vomiting in human and in animals
5-HT
3
receptors are widely distributed in the mammalian central, peripheral and enteric nervous systems and have also been found on cells of the immune system. The enteric nervous system resides within the walls of the gastrointestinal tract. 5-HT
3
receptors have been found to play an important role in the control of vomiting in a variety of mammals including humans (Veyrat-Follet, C., Farinott, R. & Palmer, J. L., 1997, Drugs 53(2):206-234). The receptors are present in the part of the brain that is involved in controlling vomiting as well as in the gastrointestinal tract. Receptors at both locations have been shown to be involved in vomiting. It is thought that 5-HT released from the enterochromaffin cells of the gastrointestinal mucosa acts on 5-HT
3
receptors to initiate the vomiting reflex. Chemotherapy and radiotherapy, two important clinical causes of vomiting, may cause release of 5-HT from the enterochromaffin cells. Chemotherapeutic agents also appear to act directly on the chemoreceptor trigger zone of the vomiting center in the brain that then feeds onto neurons containing 5-HT
3
receptors to initiate vomiting.
Currently unidentified physiological roles of 5-HT
3
receptors
It is only relatively recently that 5-HT
3
receptors were identified. The only well described physiological role for these receptors is that of the control of vomiting as described above. However, since the receptors are so widely distributed throughout the central nervous system, including numerous regi
Criares Theodore J.
Kim Jennifer
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