Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-03-20
2004-06-29
Kunz, Gary (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C530S326000, C530S300000, C514S002600
Reexamination Certificate
active
06756205
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of vasoactive compounds and their antagonists. In particular, this invention relates to antagonists of the vasoactive peptide CGRP and other members of the CGRP superfamily.
BACKGROUND OF THE INVENTION
The calcitonin gene related peptide (CGRP) is a sensory neuropeptide with potent vasodilatory and cardiotonic action as described in U.S. Pat. No. 4,530,838 to Evans et al. The peptide exists in two forms (denoted &agr; and &bgr;). &agr;-CGRP is produced by the calcitonin gene (Amara et al.
Nature
298:240-244, 1982 and Rosenfeld et al.
Nature
304:129-135, 1983) while &bgr;-CGRP is the product of a separate gene (Amara et al.
Nature
298:240-244, 1985 and Steenbergh et al.
FEBS Lett.
183:403-407, 1985). The human &bgr;-form and &agr;-form differ by three amino acids.
CGRP is concentrated in those areas of the body receiving sensory input from the dorsal horn with limited amounts associated with autonomic input. The peptide is present in the brain in the nuclei of sensory and motor cranial nerves and in cell bodies in the hypothalamus, preoptic area, ventromedial thalamus, hippocampus, and the like. CGRP is found in both sensory and motor nerves of the peripheral nervous system. The peptide is found in the skin, blood vessels, heart, gastrointestinal tract, tongue, esophagus, pancreas, salivary glands, lungs, kidney and other organs (Poyner, D.
Pharmac. Ther.
56:23-51, 1992).
The release of CGRP from sensory nerve endings in inflammatory reactions can result in the local acceleration of microhemodynamic changes including vasodilation and permeability of the microcirculation resulting in plasma exudation and the release of humoral factors and inflammatory cells to the site of injury. CGRP has been used as a vasodilator in animal models of subarachnoid hemorrhage and in trials involving human subjects with congestive heart failure. CGRP administration produced hypotension associated with moderate tachycardia in hypertensive humans (Jian et al.
Chin. Med. J
102:897-901, 1989). CGRP has also been used as a potent dilator of the coronary circulation (Ezra et al.,
Eur. J Pharmacol.,
1987). In contrast to nitrates, which have also been used as vasodilators, CGRP results in dilation by both endothelium-dependent and endothelium-independent mechanisms. Also, in contrast to nitrates, such as sodium nitroprusside, tolerance to CGRP has not been noted Bény et al.
Regul. Pept.
25:25-36, 1989). CGRP has been demonstrated to improve the ability of patients to participate in exercise programs in patients with chronic stable angina (Uren et al.
Cardiovasc. Res.
27:1477-1481, 1993).
CGRP has a number of problems as a therapeutic. CGRP is nonselective, inactive in oral form, generally has a short duration of action and has a number of side effects that can include uncontrolled hypotension (Feuerstein et al.
Can. J. Physiol. Pharmacol.
73:1070-1074, 1995).
CGRP has been implicated in migraines, diabetes, sepsis and inflammation. Migraines are noted for the strength of the headache that ensues with its pathology. Most believe that the headache associated with migraines results from the profound cerebral vasodilation. CGRP containing nerve fibers innervate cerebral and dural vessels where CGRP is believed to prolong vasodilation. (Moskowitz
Trends Pharmacol. Sci.
13:307-311, 1992). Elevated CGRP was found in the jugular vein blood of patients with migraines during a period where the patients complained of migraine symptoms, including headaches. For these reasons, CGRP antagonists have been proposed as a method for blocking cerebrovascular CGRP receptors and thus blocking the vasodilation causing migraine.
CGRP has also been postulated to be a potent indirect antagonist of insulin effects on glucose metabolism and CGRP was shown to produce insulin resistance in rat studies (Molina et al.
Diabetes
39:260-265, 1990). For this reason CGRP has recently been implicated in Type II diabetes mellitus and to abnormalities associated with carbohydrate metabolism and hyperglycemia. CGRP has also been implicated in the hemodynamic derangements associated with endotoxemia and sepsis resulting from a variety of infectious diseases. Animals exposed to lipopolysaccharide (LPS) had elevated levels of CGRP and this coincided with hypotension and tachycardia in these animals (Joyce et al.
Surgery
108:1097-1101, 1990 and Griffin et al.
Circ. Shock
38:50-54, 1992).
CGRP binds to a number of different receptors, some of which have been characterized. Radioligand binding studies to assess CGRP affinity for CGRP receptors is well known in the literature (Poyner, D. R.
Pharmac. Ther.
56:23-51, 1992). As stated in Poyner et al., a problem associated with studies to identify CGRP receptors is that lack of suitable CGRP receptor binding analogs and it is accepted that the use of CGRP antagonists is a useful way of classifying CGRP receptors. The art recognizes that there are a limited number of antagonists and that it would be desirable to have more CGRP antagonists to further classify and understand CGRP activity.
Molecules that compete for the CGRP receptor are known. These include, for example, [Tyr°]CGRP(28-37) and CGRP(8-37). Other molecules that compete for the CGRP receptor include peptides comprising the sequence of CGRP but that lack at least the first five amino acids of the CGRP amino acid sequence. [Tyr°]CGRP(28-37) was able to antagonize all forms of CGRP tested but with different potencies. Other molecules that compete for the CGRP receptor are provided elsewhere in this disclosure.
CGRP antagonists includes peptides from CGRP including amino acids 8-37 of &bgr;- CGRP (Park et al.
Am. J. Physiol.
1989) having the amino acid sequence: VTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 1) and peptides from &agr;-CGRP including amino acids 8-37 and having the amino acid sequence VTHRLAGLLSRSGGMVKSNFVVPTNVGSKAF (SEQ ID NO:2) &bgr;-CGRP(8-37) has been used to counteract the effects of CGRP. For example, CGRP(8-37) has been shown to reverse the hypotension and tachycardia produced by administration of LPS to rats (Huttemeir, et al.
Am. J. Physiol.
265:H767-H769, 1993). In addition, CGRP(8-37) has some activity against amylin (Gardiner et al. Diabetes 40:948-951, 1991). The affinity for CGRP(8-37) varies between tissues. For example, data indicates that the affinity of CGRP(8-37) for mesenteric artery, kidney, heart and skeletal muscle is somewhat higher than the affinity of CGRP(8-37) for adipocytes and descending colon (Poyner, D.
Trends in Pharm. Sci.
16:424-428, 1995).
REFERENCES:
patent: 4530838 (1985-07-01), Evans et al.
patent: 5503989 (1996-04-01), Bibbs et al.
patent: 5580953 (1996-12-01), Albrecht et al.
patent: 5625032 (1997-04-01), Gaeta et al.
Aiyar et al., “Differential Calcitonin Gene-Related Peptide (CGRP) and Amylin Binding Sites in Nucleus Accumbens and Lung: Potential Models for Studying CGRP/Amylin Receptor Subtypes”,J. Neurochem. 65:1131-1138, 1995.
Aiyar et al., “Identification and Characterization of Calcitonin Gene-Related Peptide Receptors in Porcine Renal Medullary Membranes”,Endocrinology129:965-969, 1991.
Amara et al. “Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products”,Nature298:240-244, 1982.
Beaumont et al., “Regulation of muscle glycogen metabolism by CGRP and amylin: CGRP receptors not involved”,Br. J. Pharmacol. 115:713-715, 1995.
Bény et al., “Effects of substance P, calcitonin gene-related and capsaicin on tension and membrane potential of pig coronary artery in vitro”,Regulatory Peptides, 25:25-36, 1989.
Bockman, C.S. et al., “Binding and Functional Characterization of Alpha-2 Adrenergic Receptor Subtypes on Pig Vascular Endothelium”,J. Pharmacol. Exp. Ther. 267: 1126-1133, 1993.
Champion et al., “Adrenomedullin-(22-52) antagonizes vasodilator responses to CGRP but not adrenomedullin in the cat”,Am. J. Physiol. 272:R234-242, 1997.
Collyear, K. et al., “Predicted structure of the bovine calcitonin gene-related peptide an
Abel Peter W.
Saha Shankar
Smith Derek David
Creighton University
Jiang Dong
Kunz Gary
Mueting Raasch & Gebhardt, P.A.
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