GB2324961A - Use of neuropeptide Y receptor agonists for treating migraine - Google Patents
Use of neuropeptide Y receptor agonists for treating migraine Download PDFInfo
- Publication number
- GB2324961A GB2324961A GB9809555A GB9809555A GB2324961A GB 2324961 A GB2324961 A GB 2324961A GB 9809555 A GB9809555 A GB 9809555A GB 9809555 A GB9809555 A GB 9809555A GB 2324961 A GB2324961 A GB 2324961A
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- GB
- United Kingdom
- Prior art keywords
- npy
- receptor
- agonist
- neuropeptide
- migraine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
Compounds which are agonists of the neuropeptide Y (NPY) receptor, including NPY itself, are effective agents in the treatment and/or prevention of migraine and associated conditions.
Description
USE OF NEUROPEPTIDE Y RECEPTOR AGONISTS FOR
TREATING MIGRAINE
The present invention relates to a new use for neuropeptide Y (NPY) or an agonist of the NPY receptor. More particularly, the invention concerns the use of NPY or compounds which are agonists for the NPY receptor in the treatment and/or prevention of migraine and associated conditions.
Neuropeptide Y (NPY) is a 36-residue amidated peptide. It is anatomically co-distributed and co-released with noradrenaline in and from sympathetic postganglionic neurones. Stimulation of the sympathetic nervous system under physiological circumstances such as exercise or exposure to the cold promotes an elevation of both noradrenaline and NPY.
NPY is believed to act in the regulation of appetite control and vascular smooth muscle tone, as well as in the regulation of blood pressure. NPY also decreases cardiac contractility. Congestive heart failure and cardiogenic shock are believed to be associated with release of
NPY into the bloodstream. Regulation of NPY levels may thus be beneficial in the management of these disease states.
At the cellular level, NPY binds to a G-protein coupled receptor. At least five subtypes of the NPY receptor family have been isolated and assigned on the basis of their pharmacological and physiological properties. The Y1 receptor subtype is stimulated by NPY or peptide YY (PYY) and appears to be the major vascular NPY receptor subtype. The
DNA encoding the Y1 subtype has been cloned (WO 93/09227) and shown to encode a G-protein coupled receptor (Larhammar et al., J. Biol Chem., 1992, 267, 10935; and Herzog et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 5794). The Y2 receptor subtype is stimulated by C-terminal fragments of
NPY or PYY and is abundantly expressed both centrally and peripherally.
The DNA encoding the Y2 subtype has been isolated by expression cloning (WO 95/21245). The Y3 receptor subtype is exclusively responsive to NPY and has been shown to occur in adrenal medulla, heart and brain stem.
More recently, the Y4 (WO 95/17906) and Y5 (WO 96/16542) subtypes of the NPY receptor have been isolated by molecular cloning techniques.
Further subtypes of the NPY receptor family are predicted to exist, based on pharmacological and physiological evidence.
NPY is involved in the regulation of eating behaviour, and is known to be an extremely potent orixigenic agent. When administered intracerebroventricularly or injected into the hypothalamic paraventricular nucleus (PVN) it elicits eating in satiated rats, and intraventricular injection of antisera to NPY decreases eating behaviour.
NPY has been shown to stimulate appetite in a variety of species and at different stages of development. Other effects on energy metabolism include decreased thermogenesis and body temperature, and increased white fat storage and lipoprotein lipase activity. NPY levels in the PVN increase upon fasting, before scheduled meals, and in both streptozotocininduced and spontaneous diabetes. In addition, NPY levels are elevated in genetically obese and hyperphagic Zucker rats. It has accordingly been suggested that agents which are ligands for the appropriate NPY receptor subtype might be effective in the treatment of obesity and diabetes, and eating disorders such as anorexia and bulimia.
Other disorders for which therapeutic treatment with a suitable
NPY receptor ligand has been proposed include anxiety, hypertension, cocaine withdrawal, congestive heart failure, memory deficits, cardiac and cerebral vasospasm, pheochromocytoma and ganglioneuroblastoma, as well as Huntington's, Alzheir *r's and Parkinson's diseases.
Nowhere in the prior art available to date, however, has there been any disclosure or suggestion that NPY or an agonist of NPY receptors might be beneficial in the treatment and/or prevention of migraine and associated conditions.
Although the precise mechanisms involved in the pathogenesis of migraine are not fully understood, it is generally recognised that headache pain is vascular in origin, probably arising from blood vessels of the dura mater and large cerebral arteries. Cranial blood vessels are densely innervated by trigeminal sensory neurones that have been shown to contain the potent vasodilator and pro-inflammatory peptide, calcitonin gene-related peptide (CGRP), and the inflammatory neurokinins, substance P and neurokinin A. In animals, stimulation of trigeminal nerve fibres evokes vasodilation and plasma protein extravasation within the dura mater, presumably mediated via release of these proinflammatory neuropeptides. Clinically effective anti-migraine drugs, such as the ergot alkaloids and sumatriptan, have been found to inhibit neurogenic extravasation within the dura evoked by stimulation of the trigeminal ganglion but not extravasation evoked by substance P injection, suggesting that they block neurogenic extravasation by a presynaptic action to inhibit the release of neuropeptides (Saito et al., Ann. Neurol., 1988, 24, 732; and Buzzi & Moskowitz, Br. J. Pharmacol., 1990, 99, 202).
This effect, mediated via activation of 5-HTls/lD receptors located on the trigeminal sensory nerve endings, has been suggested as a possible mechanism by which these compounds exert their anti-migraine action (Buzzi & Moskowitz, Cephalalgia, 1991, 11, 165). It is believed that 5-HTlsllD agonists such as sumatriptan confer their therapeutic action by reducing the diameter of painfully distended cranial blood vessels (Humphrey & Feniuk, Trends Pharmacol. Sci., 1991, 12, 444).
Using the recently-developed technique of direct measurement of dural vessel diameter in the rat using intravital microscopy (Williamson et al., Br. J. Pharmacol., 1996, 117, 271P), it has now been found, surprisingly, that intravenous administration of NPY is capable of blocking neurogenic vasodilation in the dura mater. This finding demonstrates that NPY or an agonist of the NPY receptor can be of benefit in the treatment and/or prevention of migraine and associated conditions, including cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension headache and paediatric migraine.
The present invention accordingly provides the use of NPY or an agonist of the NPY receptor for the manufacture of a medicament for the treatment and/or prevention of migraine and associated conditions.
The present invention also provides a method for the treatment and/or prevention of migraine and associated conditions, which method comprises administering to a patient in need of such treatment an effective amount of NPY or an agonist of the NPY receptor.
As discussed above, five discrete subtypes (Y1 to Y5) of the neuropeptide Y receptor have been isolated and characterized to date. The expression "agonist of the NPY receptor" as used herein will accordingly be understood to relate to compounds which are selective agonists of one or more of the NPY receptor subtypes relative to the other subtypes, or to compounds which are non-selective agonists of the NPY receptor. Indeed, as will be appreciated, NPY itself is an example of a compound which interacts non-selectively with the various subtypes of the NPY receptor.
Agonists of the NPY receptor of use in the present invention may be any NPY receptor agonists known from the art. Representative classes of specific compounds which are agonists of the NPY receptor are described, for example, in WO 96/40660; WO 96/14307; WO 95/00161; WO 94/00486;
US-5,569,742; EP-A-0355793; JP-A-06116284; and CA-A-2134428.
For the effective treatment and/or prevention of migraine and associated conditions, a pharmaceutical composition may be provided which comprises NPY or an agonist of the NPY receptor in association with a pharmaceutically acceptable carrier. Suitable pharmaceutical compositions may conveniently be adapted for administration orally, rectally or parenterally, e.g. intravenously. For oral adminstration, the formulation may be presented in the form of tablets, pills, capsules, powders or granules; for parenteral administration, sterile parenteral solutions or suspensions may conveniently be utilised; and for rectal administration, the formulation may conveniently be presented in the form of suppositories.
The compositions may be formulated by conventional methods well known in the pharmaceutical art, for example as described in Remington:
The Science and Practice of Pharmacy, Mack Publishing Company, 19th
Edition, 1995.
For use in the treatment and/or prevention of migraine and associated conditions, NPY or an agonist of the NPY receptor may suitably be administered at a daily dosage of about 0.001 to 100 mg/kg, typically about 0.002 to 10 mg/kg, more particularly about 0.005 to 1.0 mg/kg, and especially about 0.01 to 0.1 mg/kg. The active ingredient will typically be administered on a regimen of 1 to 4 times per day.
If desired, NPY or an agonist of the NPY receptor as defined herein may be co-administered with another medicament, in particular a known anti-migraine agent which elicits its effects by activating the 5-HTls/lD receptor. In this context, examples of specific 5-HTlsllD receptor agonists include sumatriptan (described in GB 2,162,522), naratriptan (GB 2,208,646), zolmitriptan (WO 91/18897), rizatriptan (EP 0,497,512), eletriptan (WO 92/06973) and almotriptan (WO 94/02460). When coadministered, the combination of a 5-HTls/1D receptor agonist and of NPY or an agonist of the NPY receptor may be presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the molar ratio of the 5-HTls/lD receptor agonist to NPY or to the agonist of the NPY receptor will suitably be approximately 1 to 1. Preferably, this ratio will be between 0.001 to 1 and 1000 to 1, and especially from 0.01:1 to 100:1. The 5-HTIB/1D receptor agonist will suitably be administered in a standard dosage known from the art to elicit an acceptable anti-migraine effect.
Specific aspects of the invention will now be described with reference to the accompanying drawing, Figure 1, which shows the effect of neuropeptide Y on neurogenic vasodilation of dural blood vessels in the anaesthetised rat.
Surgical preparation
Male Sprague-Dawley rats (300-400 g) were anaesthetised throughout terminal experiments with pentobarbitone sodium (initially 60 mg kgl i.p., then 18 mg kgl hr-1, continuous i.v. infusion). A femoral artery and both femoral veins were cannulated to record blood pressure, for intravenous injection of drugs and for infusion of anaesthetic, respectively.
Rats were placed in a stereotaxic frame, the skull exposed and the right parietal bone thinned by drilling with a saline-cooled drill, until the blood vessels of the dura were clearly visible through the intact skull. The cranial window was covered in mineral oil (37 oC) and a branch of the middle meningeal artery viewed using an intravital microscope (Microvision
MV2100, UK) and the image displayed on a television monitor. Dural blood vessel diameter was continuously measured using a video dimension analyser (Living Systems Instrumentation, USA) and displayed with mean arterial blood pressure (MABP) on a chart recorder and a data analysis system (MI2, Modular Instruments, UK). A bipolar stimulating electrode (NE 200X, Clark Electromedical) was placed on the surface of the cranial window approximately 200 m from the vessel of interest.
Experimental protocol
Prior to the start of experiments the surface of the cranial window was stimulated at 5 Hz, 1 ms for 10 seconds (Grass S88 stimulator, Grass
Instruments, USA) with increasing voltage until an intensity was reached at which a maximal dilation was observed. The stimulus current delivered was also measured by voltage drop across a resistance using an oscilloscope.
In neurogenic vasodilation studies an initial control dilation was performed followed by 2 further stimulations at 20 minute intervals. NPY was injected intravenously at 1 ptg kgol and 10 llg kg l (over 1 minute) 15 min prior to the second and third stimulations, respectively.
Data analysis
Dural vasodilation evoked by electrical stimulation of the cranial window was calculated as percentage increase in vessel diameter from baseline. Values presented are means + sem. The effect of NPY on neurogenic vasodilation was assessed by comparing the control responses to those evoked after drug treatment using ANOVA and paired t-tests (BMDP statistical software). In addition, to investigate the effect of NPY on dural vessel diameter per se the actual diameter values (in arbitrary units) prior to control and subsequent dilations were compared using ANOVA and paired t-tests. The effects of NPY (10 g kg-l) on MABP were calculated as percentage changes from the pre-NPY baseline MABP. Values of less than 0.05 were considered to be statistically significant.
Effect of NPY on neurogenic vasodilation (Fig. 1)
Electrical stimulation (85-275 pA) of the cranial window elicited a 113 + 9 % (n = 6) increase in dural blood vessel diameter. Pretreatment with NPY at a dose of 10 g kgl, i.v. elicted a 55 + 5 % increase in diameter, which represented a 51 % inhibition in neurogenic vasodilation as compared to control.
Conclusion
These studies demonstrate that NPY selectively inhibits neurogenic vasodilation of dural blood vessels in the anaesthetised rat.
Claims (7)
1. The use of neuropeptide Y (NPY) or an agonist of the NPY receptor for the manufacture of a medicament for the treatment and/or prevention of migraine and associated conditions.
2. The use as claimed in claim 1 wherein the medicament is adapted for co-administration of a 5-HTlsllD receptor agonist.
3. The use as claimed in claim 2 wherein the 5-HT1B/1D receptor agonist is sumatriptan, naratriptan, zolmitriptan, rizatriptan, eletriptan or almotriptan, or a pharmaceutically acceptable salt thereof.
4. The use as claimed in claim 3 wherein the 5-HTls/lD receptor agonist is rizatriptan benzoate.
5. A pharmaceutical composition comprising neuropeptide Y (NPY) or an agonist of the NPY receptor in combination with a 5-HTlsllD receptor agonist.
6. A composition as claimed in claim 5 wherein the 5-HTlsllD receptor agonist is sumatriptan, naratriptan, zolmitriptan, rizatriptan, eletriptan or almotriptan, or a pharmaceutically acceptable salt thereof.
7. A composition as claimed in claim 6 wherein the 5-HTlsllD receptor agonist is rizatriptan benzoate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9709815A GB9709815D0 (en) | 1997-05-14 | 1997-05-14 | Therapeutic method |
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| Publication Number | Publication Date |
|---|---|
| GB9809555D0 GB9809555D0 (en) | 1998-07-01 |
| GB2324961A true GB2324961A (en) | 1998-11-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9709815A Pending GB9709815D0 (en) | 1997-05-14 | 1997-05-14 | Therapeutic method |
| GB9809555A Withdrawn GB2324961A (en) | 1997-05-14 | 1998-05-05 | Use of neuropeptide Y receptor agonists for treating migraine |
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| Application Number | Title | Priority Date | Filing Date |
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| GB9709815A Pending GB9709815D0 (en) | 1997-05-14 | 1997-05-14 | Therapeutic method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003018009A1 (en) * | 2001-08-27 | 2003-03-06 | Astrazeneca Ab | A combination of quetiapine and zolmitriptan |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997020823A2 (en) * | 1995-12-01 | 1997-06-12 | Novartis Ag | 2-amino quinazoline derivatives as npy receptor antagonists |
-
1997
- 1997-05-14 GB GB9709815A patent/GB9709815D0/en active Pending
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1998
- 1998-05-05 GB GB9809555A patent/GB2324961A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997020823A2 (en) * | 1995-12-01 | 1997-06-12 | Novartis Ag | 2-amino quinazoline derivatives as npy receptor antagonists |
Non-Patent Citations (2)
| Title |
|---|
| BIOSIS Accession No: 97143848 & Headache 34(1), pages 35-40 (1994) * |
| Chemical Abstracts 127:108941 & WO 97/20823 A2 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003018009A1 (en) * | 2001-08-27 | 2003-03-06 | Astrazeneca Ab | A combination of quetiapine and zolmitriptan |
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| GB9809555D0 (en) | 1998-07-01 |
| GB9709815D0 (en) | 1997-07-09 |
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