Subunit Selective NMDA Receptor Antagonists For The Treatment Of Neurological Conditions

Abstract

Provided are compounds, pharmaceutical compositions and methods of treating or preventing disorders associated with NMDA receptor activity, including schizophrenia, Parkinson's disease, cognitive disorders, depression, neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurodegeneration. Compounds of the general Formulas A-E, and pharmaceutically acceptable salts, esters, prodrugs or derivatives thereof are disclosed.

Description

FIELD OF THE INVENTION[0001]The present invention is in the area of NMDA receptor antagonists that can be used to treat a wide range of neurological diseases and conditions, and includes methods and compositions for the treatment of neurological disorders involving NMDA receptors.BACKGROUND OF THE INVENTION[0002]The glutamate receptor gene family encodes ligand-gated ion channels that can be divided into three classes (AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate, and NMDA (N-methyl-D-aspartic acid)) on the basis of agonist pharmacology and molecular structure (Dingledine et al. 1999; Qian & Johnson 2002; Erreger et al 2004; Wollmuth & Sobolevsky 2004). NMDA receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system, and have garnered considerable attention because of their prominent role in many normal brain functions, including synaptic plasticity (Lisman 2003; Miyamoto 2006), frequency encoding of i...

AI Technical Summary

Problems solved by technology

Chronic pain, including neuropathic pain such as that due to injury of peripheral or central nerves, has often proved very difficult to treat.

While NMDA-receptor antagonists might be useful to treat a number of very challenging disorders, to date, dose-limiting side effects have prevented clinical use of NMDA receptor antagonists for these conditions.

While one might anticipate that competitive antagonists that act at glutamate-binding NR2 subunits should show selectivity between different NR2 subunits, the strongly conserved nature of the ligand contact residues across the glutamate receptor family (Mayer & Armstrong 2004; Chen et al 2005) has confounded progress, and little if any subunit selectivity has been achieved for competitive glutamate site antagonists despite considerable effort.

Although there was initial enthusiasm that NVP-AAM07 was a selective competitive antagonist for NR2A over NR2B, the initial experiments did not control the concentration of agonist, which has lower potency at NR2A.

Thus, none of the competitive antagonists or channel blockers show sufficient selectivity to be useful research tools or therapeutic agents.

Because NMDA receptor activation in these structures helps to drive the overactive output pathways in Parkinson's disease, it logically follows that selective reduction in NR2D function in these nuclei may synergistically reduce the output pathway, thereby rectifying circuit imbalance.

Thinning and weakening of the bones leads to increased fracturing from minimal trauma.

The tight coupling between the osteoblastic and osteoclastic activities of the bone remodeling cycle make the replacement of bone already lost an extremely difficult challenge.

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