Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-22
2001-06-05
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S147000
Reexamination Certificate
active
06242462
ABSTRACT:
The present invention relates to a new class of glutamate receptor antagonists useful for the treatment of pain.
L-Glutamate mediates excitatory neurotransmission in the mammalian central nervous system through its action at glutamate receptors. There are two broad classes of glutamate receptors, known as the ionotropic glutamate receptor and the metabotropic glutamate receptor. Within the class of ionotropic glutamate receptor are three classes, known as the N-methyl-D-aspartate (NMDA), (R,S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoate (AMPA) and kainate (KA) receptors. Molecular biological studies have established that AMPA receptors are composed of subunits (GluR1-4) that can assemble to form functional channels. Five kainate receptors, classified as either high affinity (KA1 and KA2) or low affinity (GluR5, GluR6 and GluR7) kainate receptors have been identified. (Bleakman et al,
Molecular Pharmacology,
1996, Vol. 49, No. 4, pgs. 581-585).
European Patent Application Publication No. 590789A1 and U.S. Pat. No. 5,446,051 disclose that certain decahydroisoquinoline derivatives are AMPA receptor antagonists, and as such are useful in the treatment of many different conditions, including pain. There is no disclosure of any compound actually being tested for use in the treatment of pain.
Surprisingly, it has now been found that a compound within the scope of European Patent Application Publication No. 590789A1, namely (3S,4aR,6S,8aR)-6-[(1(2)H-tetrazol-5-yl)methoxymethyl]decahydroisoquinoline-3-carboxylic acid, is a selective GluR5 antagonist and is effective in animal models of pain. It is therefore believed that a new pharmacological class of agents, represented by (3S,4aR,-6S,8aR)-6-[(1(2)H-tetrazol-5-yl)methoxymethyl]decahydro-isoquinoline-3-carboxylic acid, has been found for the treatment of pain.
According to one aspect, therefore, the present invention provides a method for the treatment of pain, which comprises administering to a mammal in need of treatment an effective amount of a selective GluR5 receptor antagonist.
According to another aspect, the present invention provides the use of a selective GluR5 receptor antagonist for the manufacture of a medicament for the treatment of pain.
GluR5 receptor antagonists may be identified by radiolabelled ligand binding studies at the cloned and expressed human GluR5 receptor (Korczak et al., 1994, Recept. Channels 3; 41-49), by whole cell voltage clamp electro-physiological recordings of functional activity at the human GluR5 receptor (Korczak et al., 1994, Recept. Channels 3; 41-49) and by whole cell voltage clamp electro-physiological recordings of currents in acutely isolated rat dorsal root ganglion neurons (Bleakman et al., 1996,
Mol. Pharmacol.
49; 581-585).
The selectivity of compounds acting at GluR5 receptors may be determined by measurement of activity at other AMPA and kainate receptors including receptor-ligand binding studies and whole-cell voltage clamp electro-physiological recordings of functional activity at human GluR1, GluR2, GluR3 and GluR4 receptors (Fletcher et al., 1995, Recept. Channels 3; 21-31), receptor-ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluR6 receptors (Hoo et al., Recept. Channels 2; 327-338) and whole-cell voltage clamp electrophysiological recordings of functional activity at AMPA receptors in acutely isolated cerebellar Purkinje neurons (Bleakman et al., 1996,
Mol. Pharmacol.
49; 581-585) and other tissues expressing AMPA receptors (Fletcher and Lodge, 1996,
Phannacol. Ther.
70; 65-89).
Preferably, the selective GluR5 receptor antagonist has a binding affinity of at least 10 fold greater for GluR5 than that for other glutamate receptors, more preferably at least 100 fold greater.
The selective GluR5 antagonist for use according to the invention may be a single compound or combination of compounds capable of functioning as an antagonist that is selective for the GluR5 receptor over other ionotropic glutamate receptors. For example, it may be a combination of a compound capable of functioning as an antagonist at the GluR5 receptor and one or more other glutamate receptors in combination with one or more compounds capable of blocking its actions at the one or more other ionotropic glutamate receptors. Preferably, the selective GluR5 antagonist is a single compound.
The following compounds have been found to be selective GluR5 receptor antagonists and are therefore preferred for use according to the invention: 3SR,4aRS,6SR,8aRS-6-((((1H-tetrazole-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, 3S,4aR,6S,8aR-6-((((1H-tetrazole-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,-7,8,8a-decahydroisoquinoline-3-carboxylic acid, 3SR,4aRS,6SR,8aRS-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8, 8a-decahydroisoquinoline-3-carboxylic acid and 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,-5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
The results of evaluating the activity of the aforementioned decahydroisoquinoline derivatives at the GluR5 receptor and other ionotropic glutamate receptors in the tests described above are given in Tables 1 and 2 below.
TABLE 1
Selectivity Profile for Compounds of the Invention in Binding Studies
Cell lines (HEK293 cells) stably transfected with human GluR5 receptors were employed. Displacement of 3H AMPA by increasing concentrations of test compound was used on GluR1-4-expressing cells and 3H kainate (KA) on GluR5 and expressing cells. Estimated activity (Ki) in nM was as follows.
Test
Compound
G1uR1
G1uR2
G1uR3
G1uR4
G1uR5
G1uR6
A*
150686 ±
35337 ±
47793 ±
31606 ±
3061 ±
6 ± 5%
49789 (3)
6163 (3)
8770 (3)
5914 (3)
1038 (3)
displ @
100 &mgr;M (3)
B*
—
—
—
—
5823 (2)
—
C*
21% at
55% at
—
23% at
6810
—
1 mM
1 mM
1 mM
A - 3SR, 4aRS, 6SR, 8aRS-6-[(1(2)H-tetrazol-5-yl)methoxy-methyl]decahydroisoquinoline-3-carboxylic acid (average of 3 results)
B - Compound of Example 1 (average of 2 results)
C - 3SR, 4aRS, 6SR, 8aRS-6-(((4-carboxy)phenyl)methyl)-1,2,3-4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (one result only)
D - Compound of Example 2
— Not tested
TABLE 2
Selectivity Profile for Compounds of the Invention in Electrophysioloaical Studies
Functional studies were carried out on HEK293 cells stably transfected with human GluR receptors and on acutely isolated dorsal root ganglion neurons (DRG) using patch-clamp technology (Bleakman et al., 1996,
Mol. Pharmacol.,
49, 581-585). IC50 values (&mgr;M) for test Compound A were estimated for GluR1-4 vs 100 &mgr;M AMPA and GluR5 and GluR6 vs 100 &mgr;M KA with the following results:
Test
Compound
G1uR1
G1uR2
G1uR3
G1uR4
G1uR5
G1uR6
DRG*
A
>100
>100
>100
>100
3.9 ± 0.5
>100
0.60 ± 0.06
D
—
—
—
>100
—
>100
0.98 ± 0.07
*Based on % inhibition of 30 &mgr;M kainate induced current.
The forms of pain which may be treated according to the invention include severe, chronic, intractable and neuropathic pain.
The compounds 3S,4aR,6S,8aR-6-((((1H-Tetrazole-5-yl)methyl)oxy)methyl)1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid; and 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid and their pharmaceutically acceptable salts are believed to be novel and are provided as a further aspect of the invention. The invention also provides a pharmaceutical composition comprising one of these compounds and a pharmaceutically acceptable diluent or carrier. They may be prepared, and formulated into pharmaceutical compositions, by the general methods described in European Patent Application No. 590789A1 and U.S. Patent No. 5,446,051.
The ability of selective GluR5 receptor antagonists to treat pain in mammals may be demonstrated using the well known formalin, tail flick and acetic acid-induced writhing tests.
1) Formalin Test
Male Sprague-Dawley rats (200-250 g; Charles River, Portage, Mich. ) were housed in group
Bleakman David
Helton David R.
Lodge David
Ornstein Paul L
Smriti Iyengar
Eli Lilly and Company
Reamer James H.
Wilson Alexander
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