Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-08-16
2003-11-25
Low, Christopher S. F. (Department: 1653)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024330, C435S006120, C435S070100, C530S300000, C530S324000, C530S858000, C514S012200, C514S021800
Reexamination Certificate
active
06653460
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel class of peptide compounds that specifically block class E voltage-gated calcium channels and to methods for blocking such channels. The invention also, relates to therapeutic treatments, such as treatment of convulsive disorders, using the compounds.
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BACKGROUND OF THE INVENTION
Voltage-gated calcium channels are present in neurons, and in cardiac, smooth, and skeletal muscle and other excitable cells. These channels are known to be involved in membrane excitability, muscle contraction, and cellular secretion, such as in exocytotic synaptic transmission. In neuronal cells, voltage-gated calcium channels have been classified by their electrophysiological as well as by their biochemical and pharmacological properties. More recently, further classification has been made based on the molecular biology of the channels. Calcium channels are generally classified according to their electrophysiological properties as Low-voltage-activated (LVA) or High-voltage-activated (HVA) channels. HVA channels are currently known to comprise at least three groups of channels, known as L-, N- and P/Q-type channels. These channels have been distinguished one from another electrophysiologically as well as bio-chemically on the basis of their pharmacology and ligand binding properties. Thus, dihydropyridines, diphenyl-alkylamines and piperidines bind to the alpha
1
subunit of the L-type calcium channel and block a proportion of HVA calcium currents in neuronal tissue, which are termed L-type calcium currents. N-type calcium channels are sensitive to omega conopeptides, but are relatively insensitive to dihydropyridine compounds, such as nimodipine and nifedipine. P/Q-type channels, on the other hand, are insensitive to dihydropyridines, but are sensitive to the funnel web spider toxin Aga IIIA.
R-type calcium channels, like L-, N-, P- and Q-type channels, are activated by large membrane depolarizations, and are thus classified as high voltage-activated (HVA) channels. R-type channels are insensitive to dihydropyridines and omega conopeptides, but, like P/Q, L and N channels, are sensitive to the funnel web spider toxin AgaIVA. Immunocytochemical staining studies indicate that these channels are located throughout the brain, particularly in deep midline structures (caudate-putamen, thalamus, hypothalamus, amygdala, cerebellum) and in the nuclei of the ventral midbrain and brainstem. This channel is thought to reside primarily in neuronal cell bodies and dendrites, where it contributes to cellular electrical activity. There is now also evidence that R-type channels may be localized on pre-synaptic nerve terminals.
The molecular complex comprising neuronal voltage-sensitive calcium channels consists of a central &agr;
1
subunit, an &agr;
2
/&dgr; subunit, a &bgr; subunit and a 95 kD subunit. Molecular genetic studies have revealed at least five mRNA classes that code for &agr;
1
subunits, designated A, B, C, D, and E. These correspond to the P/Q-type (&agr;
1A
), N-type (&agr;
1B
), L-type (&agr;
1C
, &agr;
1D
), and R-type (&agr;
1E
) voltage-gated channels, as defined by electrophysiological studies. (Snutch et al. 1990, Soong et al. 1993, Tsien et al. 1991; Biel et al. 1990, Mikami et al. 1989, Perez-Reyes et al. 1989, Tanabe et al., Williams et al., 1992; Fujita et al. 1993; Mori et al. 1991, Sather et al. 1993, Stea et. al. 1994 Forti et al. 1994, Randall and Tsien 1994). The class E voltage-gated calcium channel encompasses currents characterized electrophysiologically as R-type and G2 currents.
There are no known specific or selective ligands for the Class E or R-type neuronal calcium channel. Although the spider peptide omega-Aga IIIA antagonizes this channel, it also potently blocks N, P/Q- and L-type calcium currents (Cohen et al. 1993, Ertel et al. 1994) and therefore lacks specificity. The lack of specific ligands for the channel has heretofore impeded elucidation of its role(s) in neuronal function. Table 1 summarizes antagonists of the various subtypes of voltage-gated calcium channels referred to herein.
TABLE 1
Electrophysiological
Class
C-DNA Class
Peptide Ligands
N-type
B
MVIIA (SNX-111)
GVIA (SNX-124)
MVIIC (SNX-230)
SIA
AGAIIIA
P/Q-type
A
MVIIC
SIA
AGAIIIA
AGAIVA
T-type
?
None
R-type
E
AGAIIIA
SNX-482
L-type
C
AGAIIIA (?)
?
D
AGAIIIA (?)
In view of the importance of specific calcium channels in neuronal function, it would be useful to identify pharmacological agents that specifically block the class E calcium channel. The present invention is based on the discovery of a new class of peptides that selectively block this channel. This class of compounds is exemplified herein by the novel HG peptides described herein that are derived from peptides originally isolated from
H. gigas.
SUMMARY OF THE INVENTION
The present invention relates to a novel class of peptides that selectively block class E calcium channels. More specifically, such peptides, generally referred to as class E voltage-gated calcium channel blocking
Bowersox Stephen Scott
Cong Ruth L.
Dean Robin
Hopkins William F.
Miljanich George P.
Elan Pharmaceuticals Inc.
Gorthey LeeAnn
Kam Chih-Min
Low Christopher S. F.
Perkins Coie LLP
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