P2X receptors are ionotropic receptors activated by ATP. The importance of P2X receptors in nociception is underscored by the variety of pain states in which this endogenous ligand can be released. Of the seven P2X receptors, the P2X7 is distinguished by its ability to form a large pore upon prolonged or repeated agonist stimulation. It is partially activated by saturating concentrations of ATP, whereas it is fully activated by the synthetic ATP analog benzoylbenzoic ATP (BzATP) (Bianchi et al., Eur. J. Pharmacol. Vol. 376, pages 127-138, 1999). The P2X7 receptor is expressed by presynaptic terminals in the central and peripheral nervous systems, antigen-presenting cells including macrophages, human epidermal Langerhans' cells, microglial cells and a number of tumor cell lines of varying origin (Jacobson K A, et al. “Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology”. L. Belardinelli and A. Pelleg (eds.), Kluwer, Boston, pages 149-166, 1995).
On glial cells, the P2X7 receptor has been shown to mediate release of glutamate (Anderson C. et al. Drug Dev. Res. Vol. 50. page 92, 2000). Since glutamate is known to be involved in the neurotransmission of painful sensory signals, inhibition of P2X7 may have therapeutic utility in the treatment of various pain states. Furthermore, oxidized ATP (oATP), a nonselective and irreversible P2X7 antagonist, was recently reported to possess peripherally-mediated antinociceptive properties in inflamed rats (Dell'Antonio et al. Neuroscience Lett., Vol. 327 pages 87-90, 2002). Thus, P2X7 antagonists may have utility in the treatment of a variety of pain states.
Recent data also suggested a possible role for P2X7 receptor activation in neuroinflammation and neurodegeneration (Collo G. et al. Neuropharmacology, Vol. 36, pages 1277-1283, 1997). In the central nervous system, the P2X7 receptor is predominately expressed by microglia, the resident macrophages of the brain. Recent studies indicate a role of the P2X7 receptor in the generation of superoxide in microglia, and upregulation of P2X7 receptors around β-amyloid plaques in a transgenic mouse model for Alzheimer's disease (Parvathenani et al., J. Biol. Chemistry. Vol. 278, pages 13300-13317, 2003) and in multiple sclerosis lesions from autopsy brain sections (Narcisse et al., Glia, Vol. 49, pages 245-258 (2005).
Thus, P2X7 antagonists may have utility in the treatment of neurodegenerative conditions including stroke and Alzheimer's disease.
Activation of the P2X7 receptor on cells of the immune system (macrophages, mast cells and lymphocytes) leads to release of interleukin-1β (IL-1β), giant cell formation, degranulation, and L-selectin shedding. Compounds acting at the P2X7 receptor may therefore have utility in the treatment of various disease states and conditions such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke and varicose veins.
Neuropathic pain is another type of pain different from pain involved with inflammatory or neurodegenerative conditions. Neuropathic pain is associated with any disorder affecting any segment of the nervous system. Common causes of neuropathic pain are, among others, alcoholism, amputation, cancer chemotherapy, diabetes, trigeminal neuralgia, HIV infection, multiple sclerosis, shingles and spine surgery. One of the most dramatic examples of neuropathic pain is called “phantom limb syndrome” which occurs when an arm or a leg have been removed, but the brain still gets pain messages from the missing limb.
A recent study reported the localization of P2X7 on presynaptic terminals in the central and peripheral nervous systems (Deuchars et al J. Neuroscience, Vol. 21, p 7143-7152, 2001) where its activation was linked to release of the excitatory amino acid neurotransmitter glutamate. This finding indicates a role for the P2X7 receptor in the process of neuronal synaptic transmission and therefore a potential role for P2X7 antagonists as novel therapeutic tool to treat neuropathic pain.
Oxidized ATP (oATP), a nonselective and irreversible P2X7 antagonist, was recently reported to possess peripherally mediated antinociceptive properties in inflamed rats (Dell'Antonio et al. Neuroscience Lett. Vol. 327, pages 87-90, 2002).
Studies from mice lacking P2X7 receptor resulted in absence of inflammatory and neuropathic hypersensitivity to mechanical and thermal stimuli, indicating a link between a P2X7 purinoceptor gene and inflammatory and neuropathic pain (Chessell et al., Pain, Vol 114, pages 386-396 (2005)).
Antagonists to the P2X7 receptor significantly improved functional recovery and decreased cell death in spinal cord injury (SCI) animal models. Rats with SCI were administered P2X7 receptor irreversible antagonists oATP and PPADS with a resulting decrease of histological injury and improved recovery of motor function after the lesions (Wang et al., Nature Medicine Vol. 10, pages B21-B27, 2004).
In view of the above facts, there is a need for selective P2X7 antagonist that can be efficiently used in preventing, treating, or ameliorating states as neuropathic pain, chronic inflammatory pain, inflammation and neurodegenerative conditions associated with several progressive CNS disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, multiple sclerosis as well as diminished CNS function resulting from traumatic brain injury.
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