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US20110319416A1 - Subunit Selective NMDA Receptor Antagonists For The Treatment Of Neurological Conditions - Google Patents

Subunit Selective NMDA Receptor Antagonists For The Treatment Of Neurological Conditions Download PDF

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US20110319416A1
US20110319416A1 US13/146,225 US201013146225A US2011319416A1 US 20110319416 A1 US20110319416 A1 US 20110319416A1 US 201013146225 A US201013146225 A US 201013146225A US 2011319416 A1 US2011319416 A1 US 2011319416A1
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Stephen F. Traynelis
Dennis C. Liotta
Cara Mosley
Timothy M. Acker
Sommer Zimmerman
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Emory University
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Definitions

  • 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.
  • the glutamate receptor gene family encodes ligand-gated ion channels that can be divided into three classes (AMPA ( ⁇ -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).
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • kainate kainate
  • NMDA N-methyl-D-aspartic acid
  • NMDA receptors mediate a slow, Ca 2+ -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 information (Froemke et al 2005; Kampa et al 2006; Rhodes 2006), and neuronal development (Rudhard et al 2003; Colonnese et al 2005, 2006; Waters & Machaalani 2005; Nacher & McEwen 2006).
  • NMDA receptors play an overt role in neuropathology of ischemia and traumatic brain injury (Whetsell 1996; Miyabe et al 1997; Dirnagl et al 1999; Brauner-Osborne et al 2000; Wang & Shuaib 2005).
  • Animal models of stroke and brain trauma confirm that glutamate released from affected neurons can overstimulate N-methyl-D-aspartate (NMDA) receptors, which in turn causes neuronal death. Therefore, compounds that block NMDA receptors have been considered candidates for treatment of stroke, subarachnoid hemorrhage, head injuries, and other conditions associated with tissue ischemia, hypoxia, or trauma.
  • NMDA receptors have been suggested to be involved in a wide range of neurological diseases, including schizophrenia, depression, psychosis, Huntington's disease, Alzheimer's disease, and Parkinson's disease.
  • NMDA receptors are tetrameric complexes comprised of glycine-binding NR1 subunits and glutamate-binding NR2 subunits, and NR3 (A and B) subunits.
  • the subunit composition determines the functional properties of native NMDA receptors.
  • NR1 subunit alone does not produce a functional receptor.
  • Co-expression of one or more NR2 subunits or one or more NR3 subunits is required to form functional channels.
  • the NMDA receptor requires co-agonist, glycine, to allow the receptor to function.
  • a glycine binding site is found on the NR1 and NR3 subunits, whereas the glutamate binding site is found on NR2 subunits.
  • NR2A, B, C, and D The four NR2 subunits (NR2A, B, C, and D) each endow the receptor with surprisingly divergent single channel conductances, deactivation time courses, and open probabilities (Stern et al 1992; Wyllie et al 1998; Vicini et al 1998; Erreger et al 2004; Erreger et al 2005ab).
  • NMDA receptors are largely inactive due to a voltage-dependent block of the channel pore by magnesium ions. Depolarization releases this channel block and permits passage of calcium as well as other cations.
  • NR2A- and NR2B-containing NMDA receptors are more sensitive to Mg 2+ blockade than NR2C- and NR2D-containing receptors.
  • the NMDA receptor is modulated by a number of endogenous and exogenous compounds, including sodium, potassium, and calcium ions that cannot only pass through the NMDA receptor channel but also modulate the activity of receptors. Zinc blocks the channel through NR2A- and NR2B-containing receptors in a noncompetitive and voltage-independent manner.
  • Polyamines can also either potentiate or inhibit glutamate-mediated responses (reviewed by Dingledine et al. 1999).
  • Stroke is the third leading cause of death in the United States and the most common cause of adult disability.
  • Ischemic stroke is commonly divided into thrombotic stroke, embolic stroke, systemic hypoperfusion (Watershed or Border Zone stroke), or venous thrombosis.
  • NMDA antagonists have been studied as neuroprotective agents for acute stroke. However, these agents, including dextrorphan, Selfotel and aptiganel HCl (Cerestat) all showed profiles that required halting trials of these agents.
  • Epilepsy has also long been considered a potential therapeutic target for glutamate receptor antagonists.
  • NMDA receptor antagonists are known to be anti-convulsant in many experimental models of epilepsy (Bradford 1995; McNamara, J. O. 2001).
  • NMDA receptor antagonists may also be beneficial for treating chronic pain.
  • Chronic pain including neuropathic pain such as that due to injury of peripheral or central nerves, has often proved very difficult to treat.
  • Treatment of chronic pain with ketamine and amantadine has proven beneficial, and it is believed that the analgesic effects of ketamine and amantadine are mediated by blocking NMDA receptors.
  • systemic administration of amantadine or ketamine substantially reduces the intensity of trauma-induced neuropathic pain. Small-scale double blind, randomized clinical trials corroborated that amantadine could significantly reduce neuropathic pain in cancer patients (Pud et al.
  • NMDA receptor antagonists can also be beneficial in the treatment of Parkinson's disease (Blandini and Greenamyre (1998), Fundam. Clin. Pharmacol. 12:4-12).
  • the anti-Parkinsonian drug, amantadine is an NMDA receptor channel blocker (Blanpied et al. (1997), J Neurophys 77:309-323).
  • Amantidine is purportedly useful as monotherapy for early, mild Parkinsonism, and later can be used to augment levodopa's (L-DOPA's) effects.
  • L-DOPA's levodopa's
  • amantadine reduced the severity of dyskinesias by 60% without reducing the anti-parkinsonian effect of L-DOPA (Verhagen, Metman et al.
  • NMDA receptor antagonist CP-101,606
  • CP-101,606 potentiated the relief of Parkinson's symptoms by L-DOPA in a monkey model (Steece-Collier et al., (2000) Exper. Neurol., 163:239-243).
  • NMDA receptor antagonists may also be beneficial for treating brain cancers. Rapidly-growing brain gliomas can kill adjacent neurons by secreting glutamate and overactivating NMDA receptors such that the dying neurons make room for the growing tumor, and may release cellular components that stimulate tumor growth. Studies show NMDA receptor antagonists can reduce the rate of tumor growth in vivo as w vitro models (Takano, T., et al. (2001), Nature Medicine 7:1010-1015; Rothstein, J. D. and Bren, H. (2001) Nature Medicine 7:994-995; Rzeski, W., et al. (2001), Proc. Nat'l Acad. Sci 98:6372).
  • NMDA receptor antagonists have been shown to be effective in treatment resistance depression.
  • Administration of CP101,606, an ifenprodil analog, together with paroxetine improved clinical score of treatment resistant depressed patients (Preskorn et al., 2008).
  • 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. Thus, despite the tremendous potential for glutamate antagonists to treat many serious diseases, the severity of the side effects have caused many to abandon hope that a well-tolerated NMDA receptor antagonist could be developed (Hoyte L. et al (2004) “The Rise and Fall of NMDA Antagonists for Ischemic Stroke, Current Molecular Medicine” 4(2): 131-136; Muir, K. W. and Lees, K. R. (1995) Stroke 26:503-513; Herrling, P. L., ed. (1997) “Excitatory amino acid clinical results with antagonists” Academic Press; Parsons et al. (1998) Drug News Perspective II: 523 569).
  • NMDA receptor antagonists There are four well-known classes of NMDA receptor antagonists: (1) competitive antagonists at the glycine binding site on the NR1 subunit, (2) competitive antagonists at the glutamate binding site on the NR2 subunit, (3) organic cations that bind within the ion conducting pore, and (4) noncompetitive inhibitors that selectively bind to the NR2B amino terminal domain. Of these classes of antagonists, only NR2B-selective antagonists and low potency non-selective channel blockers like memantine have so far been found to be of potential clinical use.
  • a novel series of competitive piperazine-containing glutamate analogues show weak selectivity for NR2D over NR2A (estimated Ki differs ⁇ 5-fold; Feng et al 2004; Morley et al 2005; Brothwell et al 2008). Uncompetitive pore-blocking organic cations show only modest ( ⁇ 10-fold or less) selectivity for NR2 subunits (Dravid et al 2007). Thus, none of the competitive antagonists or channel blockers show sufficient selectivity to be useful research tools or therapeutic agents.
  • Ifenprodil represents a prototypical allosteric modulator of the NMDA receptor that is highly selective (>400-fold) for the NR2B subunit.
  • This compound was originally studied as a vasodilator (Ozawa et al 1975), and subsequently recognized to be a neuroprotective NMDA receptor antagonist (Gotti et al 1988). It was proposed to act at the polyamine recognition site as a subunit-selective inhibitor of NR2B-containing NMDA receptors (Reynolds & Miller 1989; Williams 1993; Hess et al 1998).
  • Ifenprodil and its analogues bind to the amino terminal domain of the NR2B subunit (Gallagher et al 1996; Perin-Dureau et al 2002; Malherbe et al 2003; Wong et al 2005) and inhibit NMDA receptor function in a voltage-independent and non-competitive fashion (Carter et al 1988; Legendre & Westbrook 1991; Kew et al 1996).
  • ifenprodil and related analogues such as eliprodil (Scatton et al 1994), CP101,606 (Chenard et al 1995), and Ro 25-6981 (Fisher et al 1997)
  • many structurally distinct NR2B receptor antagonists have been described, including oxamides (Barta-Szalai et al 2004), 5-substituted benzimidazoles 2004), indole-2-carboxamides (Borza et al 2003), benzyl cinnamamidines (Curtis et al 2003), propanolamines (Tahirovic et al 2008), and other biaryl analogues. All of these compounds show submicromolar potency (10-250 nM) and are typically more than 400-fold selective for receptors that contain the NR2B subunit over other NR2 subunits as well as over AMPA and kainate receptors.
  • NR2B-selective allosteric modulators of NMDA I have been identified.
  • Dynorphin Koreanemitsu et al 2003
  • conantokin-G from predatory marine snails
  • Sheng et al 2007 selectively inhibit NR2B-containing receptors.
  • Extracellular polyamines potentiate, with low potency (EC50 100's ⁇ M), the function of only NR2B-containing NMDA receptors (Williams et al 1994; Traynelis et al 1995).
  • Neurosteroids also potentiate and inhibit NR2A/B receptors depending on concentration, but bind at much higher rates to closed receptors than active receptors (Horak et al 2004, 2006). In summary, it is believed that highly selective inhibitors of heterodimeric receptors containing NR2A, NR2C, or NR2D subunits are heretofore unknown.
  • Parkinson's disease is a neurodegenerative disease characterized pathologically by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a reduction in dopaminergic projection terminals to the striatum.
  • the net effect of the loss of dopaminergic input to the striatum is a disinhibition of the output nuclei of the basal ganglia. This leads to increased thalamic inhibition and decreased thalamo-cortical stimulation (reviewed by Olanow & Tatton 1999). Clinically this appears as bradykinesia or akinesia, resting tremor, rigidity, and postural disturbances.
  • NMDA receptor subunit NR2D is abundantly expressed in subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), internal globus pallidus (GPi), and cholinergic striatal interneurons (Standaert et al 1994; Wenzel et al 1996; Standaert et al 1996; Counihan et al 1998), making it an intriguing target for pharmacological intervention.
  • 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.
  • recent data is consistent with NR2D expression in substantia nigra pars compacta (Jones & Gibb 2005; Brothwell et al 2008), suggesting that blockade of NR2D might also have neuroprotective effects for dopaminergic neurons.
  • NR2C/D subunits are expressed in interneurons in the cortex and hippocampus, they are believed to be involved in a variety of neurological disorders, including epilepsy, ischemia, stroke, traumatic brain injury, neuroprotection, depression, schizophrenia and neuropsychiatric illnesses, Alzheimer's, amyolateral sclerosis, multiple sclerosis, and the like. Accordingly, specific antagonists at these receptors can be used to treat these disorders, as well as other CNS disorders mediated by these inte since motor system function and coordination are affected by these neurons, and these neurons are implicated in stroke and traumatic brain injury, such specific antagonists can be used in rehabilitation from these injuries. In addition, such specific antagonists can also be used to enhance cognition, for example, in patients who have not yet succumbed to Alzheimer's disease, and, perhaps, in normal patients seeking to improve their memory and learning skills
  • NMDA receptors of the NR2D subtype are found in the osteoblasts, and therefore, compounds which have activity at these receptors can be useful in treating bone disorders.
  • the bone-remodeling cycle occurs at particular areas on the surfaces of bones. Osteoclasts which are formed from appropriate precursor cells within bones resorb portions of bone; new bone is then generated by osteoblastic activity. Osteoblasts synthesise the collagenous precursors of bone matrix and also regulate its mineralization.
  • the dynamic activity of osteoblasts in the bone remodelling cycle to meet the requirements of skeletal growth and matrix and also regulate its maintenance and mechanical function is thought to be influenced by various factors, such as hormones, growth factors, physical activity and other stimuli. Osteoblasts are thought to have receptors for parathyroid hormone and estrogen. Ostoeclasts adhere to the surface of bone undergoing resorption and are thought to be activated by some form of signal from osteoblasts.
  • Irregularities in one or more stages of the bone-remodelling cycle can lead to bone remodelling dirorders, or metabolic bone diseases.
  • diseases are osteoporosis, Paget's disease and rickets. Some of these diseases are caused by over-activity of one half of the bone-remodelling cycle compared with the other, i.e. by osteoclasts or osteoblasts. In osteoporosis, for example, there is a relative increase in osteoclastic activity which may cause a reduction in bone density and mass.
  • Osteoporosis is the most common of the metabolic bone diseases and may be either a primary disease or may be secondary to another disease or other diseases.
  • Post-menopausal osteoporosis is currently the most common form Senile osteoporosis afflicts elderly patients of either sex and younger individuals occasionally suffer from osteoporosis.
  • Osteoporosis is characterized generally by a loss of bone density. Thinning and weakening of the bones leads to increased fracturing from minimal trauma. The most prevalent fracturing in post-menopausal osteoporotics is of the wrist and spine. Senile osteoporosis, is characterized by a higher than average fracturing of the femur.
  • Estrogen deficiency has been considered to be a major cause of post-menopausal osteoporosis. Indeed steroids including estrogen have been used as therapeutic agents (New Eng. J. Med., 303, 1195 (1980)). However, recent studies have concluded that other causes must exist (J. Clin. Invest., 77, 1487 (1986)).
  • Paget's disease is one such example.
  • NMDA receptor antagonists including NMDA receptor antagonists of Formulas A-E and pharmaceutically acceptable salts, esters, prodrugs and derivatives thereof, are provided. Also provided are compositions and methods of using these compounds to treat or prevent a variety of neurological disorders, to provide neuroprotection, to prevent neurodegeneration, to treat neuropathic pain, to control addiction, to ease the symptoms of drug withdrawal, to improve cognition, and to treat schizophrenia, psychoses, depression, and the like.
  • the compounds can be used to treat motor disorders, including tardive diskinesia, to treat bipolar and other neuropsychiatric disorders, including anxiety and depression, and can provide cognitive enhancement.
  • the compounds can be used in patients with normal NMDA receptor expression, so long as the disorder involves the NMDA receptors, and the disorders are not limited to those involving neurodegeneration.
  • the compounds are used for treating depression, bipolar disorder, obsessive compulsive disorder, neuropathic pain, stroke, traumatic brain injury, epilepsy, other neurologic events or neurodegeneration resulting from NMDA receptor activation, Parkinson's disease, Alzheimer's disease, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art or predicted to be responsive to treatment using NMDA receptor blockers.
  • the compounds are used for the prophylaxis of schizophrenia, depression, neuropathic or inflammatory pain, stroke, traumatic brain injury, epilepsy, other neurologic events or neurodegeneration resulting from NMDA receptor activation, Parkinson's disease, Alzheimer's disease, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor blockers.
  • the compounds can be administered on a prophylactic basis to a patient at risk of a disorder associated with NMDA receptor activation.
  • the compounds act as neuroprotective agents.
  • the compounds can be administered alone, or in combination or alternation with other compounds useful for treating or preventing other neurologic events or neurodegeneration resulting from NMDA receptor activation, Parkinson's disease, Alzheimer's disease, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor antagonists.
  • Osteoblasts have a relatively high concentration of NMDA 2D receptor subtype, but not other receptor subtypes.
  • the compounds described herein which are specific for the NMDA 2D receptor subtype can be used to treat bone disorders, by turning on or turning off bone formation.
  • the compounds described herein can thus enhance bone formation and bone density and have beneficial effects on the activity and differentiation of bone cells.
  • the present invention relates to a method for enhancing bone formation in a mammal in need thereof, such as a human, comprising administering to the mammal an effective amount of a compound described herein that is specific for the NMDA 2D receptor subtype.
  • the mammal may have a bone deficit or be at risk of developing a bone deficit, or have a bone remodeling disorder or is at risk of developing such disorder.
  • bone remodeling disorders include osteoporosis, Paget's disease, osteoarthritis, rheumatoid arthritis, achondroplasia, osteochodrytis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophosphatasia, fribromatous lesions, fibrous displasia, multiple myeloma, abnormal bone turnover, osteolytic bone disease and periodontal disease.
  • the bone remodeling disorder is osteoporosis, including primary osteoporosis, secondary osteoporosis, osteoporosis, male osteoporosis and steroid-induced osteoporosis.
  • the compounds can also be used to enhance bone formation in a mammal having a bone deficit which does not result from a bone remodeling disorder.
  • bone deficits may result, for example, from a bone fracture, bone trauma, or a condition associated with post-traumatic bone surgery, post-prosthetic joint surgery, post-plastic bone surgery, post-dental surgery, bone chemotherapy treatment or bone radiotherapy treatment.
  • the present invention also provides a method for increasing bone density, stimulating osteoblast differentiation, inhibiting osteoclast differentiation, activating the bone formation activity of differentiated osteoblasts, simultaneously stimulating osteoblast differentiation and inhibiting osteoclast differentiation.
  • the compounds can be administered in combination with at least one bone enhancing agent.
  • suitable bone enhancing agents include a synthetic hormone, a natural hormone, oestrogen, calcitonin, tamoxifen, a bisphosphonate, a bisphosphonate analog, vitamin D, a vitamin D analog, a mineral supplement, a statin drug, a selective oestrogen receptor modulator and sodium fluoride.
  • FIGS. 1A and B are block diagrams summarizing the circuit imbalances that develop in Parkinson's disease, and showing how inhibition of NR2D-containing receptors can at least partially rectify this imbalance.
  • the block diagram shows the main output from major basal ganglia nuclei. Red denotes inhibitory projection; green denotes excitatory projection, with relative strength indicated by line thickness.
  • B Hypothesized changes in output strength in parkinsonian brain.
  • C Antagonists of NR2D-containing NMDA receptors should reduce aberrant excitatory drive in striatal cholinergic neurons, STN neurons, GPi neurons, addressing the imbalance in these nuclei (blue circles).
  • FIG. 2 is a chart showing time course of fluorescence responses of the NR1/NR2D cell line; data points are displayed as F/FBASELINE, where F is the fluorescence measured after addition of glutamate/glycine, buffer, or 1 ⁇ M MK801 to the well. Data points are mean ⁇ SD of 4-5 wells. Final agonist concentrations were 100 ⁇ M glutamate/1 mM glycine in the presence of 30 ⁇ M of the competitive glycine antagonist 7-Cl-kynurenate.
  • FIG. 3 shows two electrode voltage clamp response amplitudes NR1/NR2A and NR1/NR2D receptors activated by maximally effective concentrations of glutamate and glycine (100, 50 ⁇ M) in increasing concentrations of the antagonist in the dihydropyrazoloquinoline class (referred to here as DPQ-1105).
  • FIG. 4 shows the concentration-effect curve for another structurally distinct inhibitor referred to as QZN987-8). All values are shown in the graphs in FIGS. 3 and 4 are mean+SEM.
  • FIG. 5A is a chart showing the construct design for the NR2D-expressing BHK cell line used in Example 8.
  • FIG. 5B is a series of photographs showing that induction of NR1 was visualized using the monoclonal mAb 54.1. The control is black, as there is no fluorescence. The 24 hour induction by DOX is shown as spots, which in a color photograph would appear as green dots indicating fluorescence.
  • FIG. 5C is a series of photographs showing Fura-2 based imaging of a BHK cell line expressing NR1/NR2D during challenge with 100 ⁇ M glutamate plus 30 ⁇ M glycine. Ratio images are shown for 340/380 nm excitation (510 nm emission) for Fura-2 before and after challenge with glutamate plus glycine.
  • FIG. 6 shows the raw data (right panel) and scatter plot (left panel) from a 96 well plate tested with 80 compounds (16 control wells) from our focused biaryl library.
  • Compound 529 is an inhibitor that we previously identified in oocyte recordings. Compound 529 was detected in the Ca 2+ -based screening assay described in Example 8.
  • NMDA receptor antagonists are useful for treating or preventing a wide variety of central nervous system disorders.
  • the antagonists, pharmaceutical compositions including the antagonists, methods for their synthesis, and methods of treatment using the antagonists, are described in detail below.
  • C 1-4 alkyl Whenever a term in the specification is identified as a range (i.e. C 1-4 alkyl), the range independently refers to each element of the range.
  • C 1-4 alkyl means, independently, C 1 , C 2 , C 3 or C 4 alkyl.
  • substituents when one or more substituents are referred to as being “independently selected from” a group, this means that can be any element of that group, and any combination of these groups can be separated from the group.
  • R 1 and R 2 can be independently selected from X, Y and Z, this separately includes the groups R 1 is X and R 2 is X; R 1 is X and R 2 is Y; R 1 is X and R 2 is Z; R 1 is Y and R 2 is X; R 1 is Y and R 2 is Y; R 1 is Y and R 2 is Z; R 1 is Z and R 2 is X; R 1 is A and R 2 is Y; and R 1 is Z and R 2 is Z.
  • NMDA receptor as used herein means a postsynaptic or nonsynaptic receptor which is stimulated, at a minimum, by the excitatory amino acids glutamate or aspartate, and glycine or serine. It is a ligand-gated receptor with a strychnine-insensitive glycine site.
  • agonist means any compound which by itself through actions at its binding site increases the flow of current through the NMDA receptor--a channel opener.
  • NMDA receptors both sites need to be occupied for the receptor to function.
  • glycine is an agonist because when the receptor has bound glutamate, glycine alone can bind to and activate the glutamate-bound receptor.
  • glutamate is an agonist because when the receptor is bound to glycine, then glutamate alone can bind and then activate the glycine-bound receptor.
  • co-agonist means any pair of compounds (for example glutamate and glycine) that bind to the same receptor complex at different sites and for which binding by both molecules is required to activate the receptor.
  • antagonist means any compound which reduces the flow of current through the NMDA receptor either by blocking the binding of an agonist, blocking the channel, causing channel closure, or binding to a site separate from the agonist binding sites and channel pore that when occupied inhibits receptor function.
  • ligand as used herein means any compound which binds to a site on the NMDA receptor.
  • halogen refers to fluorine, chlorine, bromine, and iodine atoms.
  • hydroxyl as used herein means —OH.
  • lower alkoxy as used herein means lower alkyl-O—.
  • oxo as used herein means an ⁇ O group.
  • mercapto as used herein means a —SH group.
  • aryl as used herein means an organic radical derived fi hydrocarbon, e.g., phenyl from benzene.
  • amino as used herein means —NH 2 .
  • alkyl refers to a substituted or unsubstituted, saturated, straight, branched, or cyclic (also identified as cycloalkyl), primary, secondary, or tertiary hydrocarbon, including but not limited to those of C1 to C6.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, isobutyl, tertbutyl, cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl, isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl.
  • the alkyl group can be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, sulfonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, thioether, oxime, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 2002.
  • alkyl may be optionally substituted by one or more fluoro, chloro, bromo, iodo, hydroxy, heterocyclic, heteroaryl, carboxy, alkoxy, nitro, NH 2 , N(alkyl) 2 , NH(alkyl), alkoxycarbonyl, —N(H or alkyl)C(O)(H or alkyl), —N(H or alkyl)C(O)N(H or alkyl) 2 , —N(H or alkyl)C(O)O(H or alkyl), —OC(O)N(H or alkyl) 2 , —S(O) n —(H or alkyl), —C(O)—N(H or alkyl) 2 , cyano, alkenyl, cycloalkyl, acyl, hydroxyalkyl, heterocyclic, heteroaryl, aryl, aminoalkyl, oxo, carboxyalkyl,
  • lower alkyl as used herein means an alkyl moiety having 1-9 carbon atoms, which may be straight or branched, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, amyl, isoamyl, hexyl, heptyl, octyl, nonyl, or the like.
  • cycloalkyl refers to a substituted or unsubstituted, saturated cyclic hydrocarbon, including but not limited to those of C 3 to C 12 .
  • Illustrative examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the cycloalkyl group can be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, carboxylic acid, amide, phosphonyl, phosphinyl, thioether, oxime, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 2002.
  • the cycloalkyl may be optionally substituted by one or more fluoro, chloro, bromo, iodo, hydroxy, heterocyclic, heteroaryl, carboxy, alkoxy, nitro, NH 2 , N(alkyl) 2 , NH(alkyl), alkoxycarbonyl, —N(H or alkyl)C(O)(H or alkyl), —N(H or alkyl)C(O)N(H or alkyl) 2 , —N(H or alkyl)C(O)O(H or alkyl), —OC(O)N(H or alkyl) 2 , —S(O) n —(H or alkyl), —C(O)—N(H or alkyl) 2 , cyano, alkenyl, cycloalkyl, acyl, hydroxyalkyl, heterocyclic, heteroaryl, aryl, aminoalkyl, oxo
  • halo or “halogen,” refers to chloro, bromo, iodo, or fluoro.
  • heterocyclic refers to a non-aromatic or aromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
  • heteroaryl or “heteroaromatic,” refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
  • heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole
  • the heteroaromatic or heterocyclic group can be optionally substituted with one or more substituents selected from halogen, haloalkyl, alkyl, alkoxy, hy derivatives, amido, amino, alkylamino, dialkylamino.
  • the heteroaromatic can be partially or totally hydrogenated as desired.
  • Nonlimiting examples include dihydropyridine and tetrahydrobenzimidazole.
  • the heteroaryl may be optionally substituted by one or more fluoro, chloro, bromo, iodo, hydroxy, thiol, ether, thioether, heterocyclic, heteroaryl, carboxy, alkoxy, nitro, NH 2 , N(alkyl) 2 , NH(alkyl), alkoxycarbonyl, —N(H or alkyl)C(O)(H or alkyl), —N(H or alkyl)C(O)N(H or alkyl) 2 , —N(H or alkyl)C(O)O(H or alkyl), —OC(O)N(H or alkyl) 2 , —S(O) n —(H or alkyl), —C(O)—N(H or alkyl) 2 , cyano, alkenyl, cycloalkyl, acyl, hydroxyalkyl, heterocyclic, heteroaryl, aryl,
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-tolylsulfonyl.
  • aryl refers to a carbon based aromatic ring, including phenyl, biphenyl, or naphthyl.
  • the aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, acyl, amino, halo, alkylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 2002.
  • the aryl group is optionally substituted by one or more fluro, chloro, bromo, iodo, hydroxy, heterocyclic, heteroaryl, carboxy, alkoxy, nitro, NH 2 , N(alkyl) 2 , NH(alkyl), alkoxycarbonyl, —N(H or alkyl)C(O)(H or alkyl), —N(H or alkyl)C(O)N(H or alkyl) 2 , —N(H or alkyl)C(O)O(H or alkyl), —OC(O)N(H or alkyl) 2 , —S(O) n —(H or alkyl), —C(O)—N(H or alkyl) 2 , cyano, alkenyl, cycloalkyl, acyl, hydroxyalkyl, heterocyclic, heteroaryl, aryl, aminoalkyl, oxo, carboxy, alkoxy
  • alkyl refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above.
  • alkaryl unless otherwise specified, refers to an alkyl group as defined above linked to the molecule through an aryl group as defined above.
  • acyloxyalkyl alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminoalkyl, alkylthioalkyl, amidoalkyl, aminoalkyl, carboxyalkyl, dialkylaminoalkyl, haloalkyl, heteroaralkyl, he hydroxyalkyl, sulfonamidoalkyl, sulfonylalkyl and thioalkyl are named in a similar manner.
  • alkoxy refers to a moiety of the structure —Oalkyl, wherein alkyl is as defined above.
  • acyl refers to a group of the formula C(O)R′ or “alkyl-oxy”, wherein R′ is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl.
  • alkenyl means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to (C 2 -C 8 )alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl,4- (2-methyl-3-butene)-pentenyl.
  • An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • carbonyl refers to a functional group composed of a carbon atom double-bonded to an oxygen atom: —C ⁇ O.
  • C(O) or C( ⁇ O) refers to a carbonyl group.
  • amino refers to —NH 2 , —NH(alkyl) or —N(alkyl) 2 .
  • thio indicates the presence of a sulfur group.
  • the prefix thio- denotes that there is at least one extra sulfur atom added to the chemical.
  • the prefix ‘thio-’ can also be placed before the name of a compound to mean that an oxygen atom in the compound has been replaced by a sulfur atom.
  • the terms ‘thio’ and ‘thiol’ are used interchangeably, unless otherwise indicated.
  • amido indicates a group (H or alkyl)-C(O)—NH—.
  • sulfonyl indicates an organic radical of the general formula (H or alkyl)-S( ⁇ O) 2 —(H or alkyl′), where there are two double bonds between the sulfur and oxygen.
  • sulfonamide indicates an organic radical of the general formula (H or alkyl)-S( ⁇ O) 2 —N(H or alkyl′) 2 , although the nitrogen can alternatively be bonded to aryl, aralkyl, alkaryl, or heteroaryl moieties as described herein.
  • salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects.
  • Nonlimiting examples of such salts are (a) a formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from
  • quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula —NR+A-, wherein R is H or alkyl and A is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is H or alkyl and A is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate
  • protected refers to a group that is added to an oxygen, nitrogen, or phosphorus atom, or on an acetylenic carbon (i.e., a trimethylsilyl group in place of an acetylenic proton) to prevent its further reaction or for other purposes.
  • acetylenic carbon i.e., a trimethylsilyl group in place of an acetylenic proton
  • a wide variety of oxygen, nitrogen, phosphorus, and acetylenic protecting groups are known to those skilled in the art of organic synthesis, and described in Greene and Wuts, Protective Groups in Organic Synthesis, supra.
  • the compounds typically have one of the following Formulas A-E, as shown below.
  • the compounds typically have IC 50 values in the range of 0.01 to 10 ⁇ M, 0.01 to 9 ⁇ M, 0.01 to 8 ⁇ M, 0.01 to 7 ⁇ M, 0.01 to 6 ⁇ M, 0.01 to 5 ⁇ M, 0.01 to 4 ⁇ M, 0.01 to 3 ⁇ M, 0.01 to 2 ⁇ M, 0.01 to 1 ⁇ M, 0.05 to 7 ⁇ M, 0.05 to 6 ⁇ M, 0.05 to 5 ⁇ M, 0.05 to 4 ⁇ M, 0.05 to 3 ⁇ M, 0.05 to 2 ⁇ M, 0.05 to 1 ⁇ M, 0.05 to 0.5 ⁇ M, 0.1 to 7 ⁇ M, 0.1 to 6 ⁇ M, 0.1 to 5 ⁇ M, to 3 ⁇ M, 0.1 to 2 ⁇ M, 0.1 to 1 ⁇ M, 0.1 to 0.5 ⁇ M, 0.1 to 0.4 ⁇ M, 0.1 to 0.3 ⁇ M, or 0.1 to
  • A-B is a linker moiety selected from the group consisting of
  • X is, independently, N, or C bonded to H or a substituent, J, with the proviso that no more than three of X are N;
  • Y 1 and Y 2 are, independently, selected from O, S, NR 1 , CH 2 , and CR 1 2 ;
  • R 1 and R 2 are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and hydroxy,
  • R 1 and R 2 can optionally join to form a C 3-10 heterocyclic moiety, which heterocyclic moiety can optionally include a second heteroatom selected from O, S, and N,
  • R 2 is absent when Q is O or S,
  • Z is, independently, (CH 2 ) n , CHR, CR 2 , O, S, or NR 1 ,
  • T is, independently, CHR, C(R 1 ) 2 , O, S, or NR 1 ,
  • Q is independently selected from CH, C-halo, or N, or O or S if R 2 is absent,
  • V is, independently, N or C bonded to H or a substituent J
  • J is a non-hydrogen substituent selected from the group consisting of halo (—F, —Cl, —Br, —I,), nitro, amino (NR 1 R 2 ), OR 1 , SR 1 , —R 1 , —CF 3 , —CN, —C 2 R 1 , —SO 2 CH 3 , —C( ⁇ O)NR 1 R 2 —NR′C( ⁇ O)R 1 , —C( ⁇ O)R 1 , —C( ⁇ O)OR 1 , —(CH 2 ) q OR 1 , —OC( ⁇ O)R 1 , —OC( ⁇ O)NR 1 R 2 , —NR 1 (C ⁇ Y)—NR 1 R 2 , —NR 1 (C ⁇ Y)—OH, —NR 1 (C ⁇ Y)—SH, sulfonyl, sulfinyl, —SO 2 NHR 1 , —NHSO 2 R 1 , phosphoryl, and
  • naphthyl and indole are specific ri included, and the linkages can occur at any free position on the naphthyl and indole rings.
  • Representative compounds of Formula A include the following:
  • X is, independently, N or C bonded to H or a substituent, J, with the proviso that no more than three of X are N;
  • Y 1 and Y 2 are, independently, selected from O, S, NR 1 , CH 2 , and CR 1 2 ;
  • R 1 and R 2 are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and hydroxy,
  • R 1 and R 2 can optionally join to form a C 3-10 heterocyclic moiety, whi moiety can optionally include a second heteroatom selected from O, S, and N,
  • R 2 is absent when Q is O or S,
  • Z is, independently, (CH 2 ) n , CHR, CR 2 , O, S, or NR 1 ,
  • T is, independently, CHR, C(R 1 ) 2 , O, S, or NR 1 ,
  • Q is independently selected from CH, C-halo, or N, or O or S if R 2 is absent.
  • V is, independently, N or C bonded to H or a substituent J
  • J is a non-hydrogen substituent selected from the group consisting of halo (—F, —Cl, —Br, —I,), nitro, amino (NR 1 R 2 ), SR 1 , R 1 , CF 3 , —CN, —C 2 R 1 , —SO 2 CH 3 , —C( ⁇ O)NR 1 R 2 —NR′C( ⁇ O)R 1 , —C( ⁇ O)R 1 , —C( ⁇ O)OR 1 , —(CH 2 ) q OR 1 , —OC( ⁇ O)R 1 , —OC( ⁇ O)NR 1 R 2 , —NR 1 (C ⁇ Y)—OH, —NR 1 (C ⁇ Y)—SH, sulfonyl, sulfinyl, —SO 2 NHR 1 , —NHSO 2 R 1 , phosphoryl, and azo.
  • halo —F, —Cl, —Br, —
  • thiophene particularly 2,4-disubstituted thiophene, is a particularly preferred Ar 2 ring.
  • X is, independently, N or C bonded to H or a substituent, J, with the proviso that no more than three of X are N;
  • Y is O, S, or NR 1 ,
  • R 1 and R 2 are, independently, selected from H, alkyl, alkenyl, aryl, and heteroaryl,
  • R 1 and R 2 can optionally join to form a C 3-10 heterocyclic moiety, which heterocyclic moiety can optionally include a second heteroatom selected from O, S, and N,
  • J is a non-hydrogen substituent selected from the group consisting of halo (—F, —Cl, —Br, —I,), nitro, amino (NR 1 R 2 ), OR 1 , SR 1 , —R 1 , —CF 3 , —CN, —C 2 R 1 , —SO 2 CH 3 , —C( ⁇ O)NR 1 R 2 —NR′C( ⁇ O)R 1 , —C( ⁇ O)R 1 , —C( ⁇ O)OR 1 , —(CH 2 ) q OR 1 , —OC( ⁇ O)R 1 , —OC( ⁇ O)NR 1 R 2 , —NR 1 (C ⁇ Y)—NR 1 R 2 , —NR 1 (C ⁇ Y)—OH, —NR 1 (C ⁇ Y)—SH, sulfonyl, sulfinyl, —SO 2 NHR 1 , —NHSO 2 R 1 , phosphoryl, and
  • z is a number from 0 to 3.
  • Representative compounds of Formula B include:
  • A-B is a linker moiety selected from the group consisting of
  • R 1 is, independently, H, alkyl, aryl, aralkyl, alkaryl, or heteroaryl
  • T is C(R 1 ) 2 , NR 1 , O or S
  • J is a substituent as defined herein
  • z is 0-3,
  • R 3 is independently selected from the group consisting of H, Ar 3 ,—C 1-10 straight, branched, or cyclic alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 3-10 heterocyclyl, and —O—C 1-10 alkyl,
  • R 4 is selected from the group consisting of —CO 2 R 1 , —SO 3 R 1 , —SO 2 N(R 1 ) 2 , —C(T)NR 1 2 , —OC(T)OR 1 , —SC(T)OR 1 , —NR 1 C(T)OR 1 , —NR 1 C(T)NR 1 , —SC(T)NR 1 2 , and —NR 1 C(T)NR 1 2 ,
  • X is, independently, N or C bonded to H or a substituent, J,
  • Y 1 and Y 2 are, individually, CHR, CR 2 , O, S, or NR′,
  • T is, independently, CHR, CR 2 , O, S, or NR′,
  • V is, independently, N or C bonded to H or a substituent J
  • J is a non-hydrogen substituent selected from the group consisting of halo (—F, —Cl, —Br, —I,), nitro, amino (NR 1 R 2 ), OR 1 , SR 1 , —R 1 , —CF 3 , —CN, —C 2 R 1 , —SO 2 CH 3 , —C( 50 O)NR 1 R 2 —NR′C( ⁇ O)R 1 , —C( ⁇ O)R 1 , —C( ⁇ O)OR 1 , —(CH 2 ) q OR 1 , —OC( ⁇ O)NR 1 R 2 , —NR 1 (C ⁇ Y)—NR 1 R 2 , —NR 1 (C ⁇ Y)—OH, —NR 1 (C ⁇ Y)—SH, sulfonyl, sulfinyl, —SO 2 NHR 1 , —NHSO 2 R 1 , phosphoryl, and azo, and
  • z is a number from 0 to 3.
  • a subset of compounds of Formula C has the formula below:
  • J, V, X, Y 1 , Y 2 , and z are as defined above, and n is 1-4.
  • Representative compounds of Formula C include:
  • the compounds described herein may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present invention.
  • Compounds of the present invention having a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds can exhibit polymorphism.
  • the present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric forms, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein.
  • the compounds are present as enantiomers.
  • the compound is provided as an enantiomer or mixture of enantiomers.
  • the compound is present as a racemic mixture.
  • the enantiomer can be named by the configuration at the chiral center, such as R or S.
  • the compound is present as a racemic mixture of R- and S-enantiomers.
  • the compound is present as a mixture of two enantiomers.
  • the mixture has an enantiomeric excess in R.
  • the mixture has an enantiomeric excess in S.
  • the compound is in an enantiomeric exce enantiomer.
  • the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the single enantiomer.
  • the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the R enantiomer.
  • the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the S enantiomer.
  • the compound is substantially in the form of a single enantiomer, such as the R- or S-enantiomer.
  • the phrase “substantially in the form of a single enantiomer” is intended to mean at least 70% or more in the form of a single enantiomer, for example 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in either the R- or S-enantiomer.
  • the enantiomer can be named by the direction in which it rotates the plane of polarized light. If it rotates the light clockwise as seen by the viewer towards whom the light is traveling, the isomer can be labeled (+) and if it rotates the light counterclockwise, the isomer can be labeled ( ⁇ ).
  • the compound is present as a racemic mixture of (+) and ( ⁇ ) isomers. In certain embodiments, the compound is present as a mixture of two isomers. In one embodiment, the mixture has an excess in (+). In one embodiment, the mixture has an excess in ( ⁇ ). In certain other embodiments, the compound is in an excess of the (+) or ( ⁇ ) isomer.
  • the isomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the (+) isomer.
  • the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the ( ⁇ ) isomer.
  • the compound is substantially in the form of a single optical isomer, such as the (+) or ( ⁇ ) isomer.
  • a single optical isomer such as the (+) or ( ⁇ ) isomer.
  • the phrase “substantially in the form of a single optical isomer” is intended to mean at least 70% or more in the form of a single isomer, for example 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of either the (+) or ( ⁇ ) isomer.
  • optically active forms can be prepared by, for example, resolutic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
  • Optically active forms of the compounds can be prepared using any method known in the art, including but not limited to by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • Examples of methods to obtain optically active materials include at least the following.
  • Chiral chromatography including but not limited to simulate chromatography, is used in one embodiment.
  • a wide variety of chiral stationary phases are commercially available.
  • the compounds of Formula A are members of the class O-4(phenylcabamoyl)phenyl carbothioates.
  • Analogues of 1063 are characterized by differential phenyl amide substitution (R 3 ), particularly naphthyl and indole systems, and variously alkyl substituted carbamothioates or carbamates at the para position (R 1 and R 2 ).
  • Scheme 2 details the synthesis of compounds with variability at the carbamate or carbothioate position.
  • Methyl-4-hydroxy benzoate (1) is protected with para-methoxybenzyl (PMB) ether to give 7.
  • PMB para-methoxybenzyl
  • the ester is hydrolyzed under basic conditions to give carboxylic acid 8.
  • Coupling with anilines is then performed to give amides of type 9.
  • Deprotection of the PMB group in neat trifluoroacetic acid (TFA) gives phenol 10.
  • Reaction with various carbothioyl chlorides or carbamoyl chlorides as described above yields final compounds of general structure 6.
  • Scheme 2a details the synthesis of 3,5,7-substituted amino indole d can be used in the coupling steps outlined in schemes 1 and 2.
  • a variety of nitro-substituted anilines (11) can be iodinated using iodine and silver sulfate in ethanol at room temperature (Koradin et. al (2003)).
  • the iodinated aniline (12) can then be subjected to conditions developed by Larock to yield a wide variety of 3,5,7-substituted indoles (13) (Charrier et al, (2006), Larock et al (1998)).
  • standard hydrogenation procedures reduce the nitro mom to the amino derivative found in (5a).
  • Scheme 2b outlines the general procedure for synthesizing 2,3,5,7-substituted indole derivatives for use in the coupling reactions outlined in schemes 1 and 2. Beginning with compound (12), under conditions developed by Larock et al (1998), symmetrically substituted alkynes undergo addition and cyclization to yield derivative (15) which can be readily hydrogenated to yield (5b).
  • Scheme 2c outlines a general procedure for synthesizing 2,5,7-substituted indole derivatives for use in the coupling reactions outlined above. Briefly, Sonagashira cross-coupling conditions between the iodinated aniline, (12), and acetyline derivatives with a free acetylinic hydrogen, followed by base or metal mediated cyclization are well-known to give the desired regiochemical outcome depicted by (14) (Koradin et al (2003), Cacchi, Fabrizi, (2005)).
  • Compounds of Formula A, where Z is NR′, O, or S can also be prepared, for example, by reacting an appropriately derivatized and functionalized (i.e., with desired Z substituents, as described above), and protected, Ar 1 moiety with an NHR′, OH, or SH group, with an appropriately derivatized and protected Ar 2 moiety.
  • the Ar 2 moiety includes a carboxylic acid group (or analogs where the carbonyl is replaced with C ⁇ S or C ⁇ NR′), or activated derivative thereof, and a protected amine, thiol, or hydroxy group, depending on the desired compound.
  • Activated carboxylic acid derivatives include, for example, anhydrides, which are known to participate in amidation, esterification, and thioesterification reactions. Suitable protecting groups are described in detail above.
  • a representative reaction scheme is provided below, where an activated carboxylic acid (an acid chloride) is used in an amination reaction.
  • an activated carboxylic acid an acid chloride
  • the aryl rings in this case are shown as phenyl, the coupling chemistry works with other aryl and heteroaryl rings, as described herein, so long as the J substituents either do not react with the functional groups involved in the coupling chemistry, or the J substituents are suitably protected so that they do not interfere.
  • the coupling chemistry works with other aryl and heteroaryl rings, as described herein, so long as the J substituents either do not react with the functional groups involved in the coupling chemistry, or the J substituents are suitably protected so that they do not so interfere.
  • the coupling chemistry can occur via Friedel-Crafts alkylation.
  • the reaction scheme will look similar to that shown above, but the Ar 1 ring will not be an organolithium or Grignard reagent, but rather, have a proton at the position where the lithium is shown above.
  • a Lewis acid catalyst is used for the coupling chemistry.
  • the starting aniline is PMB protected with catalytic para-toluene-sulfonic acid.
  • the acid chloride is then reacted with the protected amine to form an amide bond.
  • the resulting compound is then activated with acid, dehydrating the molecule and closing the ring.
  • the saturated ester is then mixed with the enolate, which undergoes Claisen-condensation to give the di-keto structure.
  • the di-keto molecule is then reacted with the monoacylated hydrazine to give the pyrazole-containing compound.
  • the final steps are to saponify the ester and to de-protect the amide. While this Scheme shows functionalization/derivatization on the starting materials and resulting product, other functional groups/derivatives can be present so long as they do not interfere with the chemistry, or are protected so that they do not interfere with the chemistry.
  • Mammals, and specifically humans, suffering from schizophrenia, Parkinson's disease, depression, neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration involving NMDA receptor activation, or any of the above-described conditions, and in particular suffering from neuropathic pain can be treated by either targeted or systemic administration, via oral, inhalation, topical, trans- or sub-mucosal, subcutaneous, parenteral, intramuscular, intravenous or transdermal administration of a composition comprising an effective amount of the compounds described herein or a pharmaceutically acceptable salt, ester or prodrug thereof, optionally in a pharmaceutically acceptable carrier.
  • the compounds or composition is typically administered by oral administration.
  • compounds can be administered by inhalation.
  • the compound is administered transdermally (for example via a slow release patch), or topically.
  • the compound is administered subcutaneously, intravenously, intraperitoneally, intramuscularly, parenterally, or submucosally.
  • the compound is administered in an effective dosage range to treat the target condition.
  • compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl salicylate, or orange flavoring
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier (such as a fatty oil).
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
  • the compound or its salts can also be administered orally as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, a sweetening agent (such as sucrose, saccharine, etc.) and preservatives, dyes and colorings and flavors.
  • the compounds of the invention may also be administered in specific, measured amounts in the form of an aqueous suspension by use of a pump spray bottle.
  • the aqueous suspension compositions of the present invention may be prepared by admixing the compounds with water and other pharmaceutically acceptable excipients.
  • the aqueous suspension compositions according to the present invention may contain, inter alia, water, auxiliaries and/or one or more of the excipients, such as: suspending agents, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxpropyl-methyl cellulose; humectants, e.g.
  • the compounds of the invention are in the form of an inhaled dosage.
  • the compounds may be in the form of an aerosol suspension, a dry powder or liquid particle form.
  • the compounds may be prepared for delivery as a nasal spray or in an inhaler, such as a metered dose inhaler.
  • Pressurized metered-dose inhalers generally deliver aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11, CFC-12, or the non-chlorofluorocarbons or alternate propellants such as the fluorocarbons, HFC-134A or HFC-227 with or without surfactants and suitable bridging agents.
  • Dry-powder inhalers can also be used, either breath activated or delivered by air or gas pressure such as the dry-powder inhaler disclosed in the Scher International Patent Application No. PCT/US92/05225, published 7 Jan.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include at least some of the following components: a sterile diluent (such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents); antibacterial agents (such as benzyl alcohol or methyl parabens); antioxidants (such as ascorbic acid or sodium bisulfite); chelating agents (such as ethylenediaminetetraacetic acid); buffers (such as acetates, citrates or phosphates); and/or agents for the adjustment of tonicity (such as sodium chloride or dextrose).
  • the pH of the solution or suspension can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa.
  • thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • carriers can be physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions including liposomes targeted to infected cells with monoclonal antibodies to viral a preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety).
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stea
  • the compound is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.
  • the compounds are administered less than three times daily.
  • the compounds are administered in one or two doses daily.
  • the compounds are administered once daily.
  • the compounds are administered in a single oral dosage once a day.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects.
  • An effective dose can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • a number of factors are considered including, but not limited to: the species of patient; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication.
  • Typical systemic dosages for the herein described conditions are those ranging from 0.01 mg/kg to 1500 mg/kg of body weight per day as a single daily dose or divided daily doses.
  • Preferred dosages for the described conditions range from 0.5-1500 mg per day.
  • a more particularly preferred dosage for the desired conditions ranges from 5-750 mg per day.
  • Typical dosages can also range from 0.01 to 1500, 0.02 to 1000, 0.2 to 500, 0.02 to 200, 0.05 to 100, 0.05 to 50, 0.075 to 50, 0.1 to 50, 0.5 to 50, 1 to 50, 2 to 50, 5 to 50, 10 to 50, 25 to 50, 25 to 75, 25 to 100, 100 to 150, or 150 or more mg/kg/day, as a single daily daily doses.
  • the daily dose is between 10 and 500 mg/day.
  • the dose is between about 10 and 400 mg/day, or between about 10 and 300 mg/day, or between about 20 and 300 mg/day, or between about 30 and 300 mg/day, or between about 40 and 300 mg/day, or between about 50 and 300 mg/day, or between about 60 and 300 mg/day, or between about 70 and 300 mg/day, or between about 80 and 300 mg/day, or between about 90 and 300 mg/day, or between about 100 and 300 mg/day, or about 200 mg/day.
  • the compounds are given in doses of between about 1 to about 5, about 5 to about 10, about 10 to about 25 or about 25 to about 50 mg/kg. Typical dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the compound can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action.
  • the active compounds can be administered in conjunction, i.e. combination or alternation, with other medications used in the treatment or prevention of schizophrenia, Parkinson's disease, depression, neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration involving NMDA receptor activation.
  • the compounds can be administered in conjunction (combination or alternation) with other medications used in treatment or prophylaxis of inflammatory conditions.
  • the combination can be synergistic although in other embodiments the combination is not synergistic.
  • the compounds are used in a method of treatment or prophylaxis of schizophrenia, Parkinson's disease, bipolar disorder, depression, anxiety, neuropsychiatric or mood disorders, obsessive-compulsive disorder, motor dysfunction, neuropathic pain, ischemic and hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, ischemia, hypoxia, Alzheimer's disease, pre-senile dementia, amyolateral sclerosis (ALS), Huntington's chorea, traumatic brain injury, epilepsy, and other neurologic events, neurocognitive disorders, tardive dyskinesia, motor disorders, mood disorders or neurodegeneration involving NMDA receptor activation comprising administering to a host in need thereof an effective amount of a compound described herein, optionally in a pharmaceutically acceptable carrier.
  • the compounds can be administered, alone or in a pharmaceutically acceptable carrier, to a patient suffering from, or at risk of developing the various disorders, to treat, prevent, or reduce the symptoms of or cognitive disorders
  • the compounds described herein can also generally be used to treat neurologic events and neurodegeneration, whether or not such neurologic event or neurodegeneration is associated with NMDA receptor activation.
  • the compounds are used to treat or prevent stroke or stroke damage, and can be administered under emergency care for a stroke, for maintenance treatment of stroke, and/or for rehabilitation of stroke.
  • the compounds are used to provide cognitive enhancement, in normal or cognitively deficient individuals.
  • methods are provided to treat patients with ischemic injury or hypoxia, or prevent or treat the neuronal toxicity associated with ischemic injury or hypoxia, by administering a compound or composition described herein.
  • the ischemic injury is vasospasm after subarachnoid hemorrhage.
  • a subarachnoid hemorrhage refers to an abnormal condition in which blood collects beneath the arachnoid mater, a membrane that covers the brain. This area, called the subarachnoid space, normally contains cerebrospinal fluid. The accumulation of blood in the subarachnoid space, and the vasospasm of the vessels which results from it, can lead to stroke, seizures, and other complications.
  • the methods and compounds described herein can be used to treat patients experiencing a subarachnoid hemorrhage. In one embodiment, the methods and compounds described herein can be used to limit the toxic effects of hemorrhage, including, for example, stroke and/or ischemia that can result from the subarachnoid hemorrhage.
  • the methods and compounds described herein can be used to treat patients with traumatic subarachnoid hemorrhage.
  • the traumatic subarachnoid hemorrhage can be due to a head injury.
  • the patients can have a spontaneous subarachnoid hemorrhage.
  • the ischemic injury is selected from, but not limited to, one of the following: traumatic brain injury, cognitive deficit after bypass surgery, cognitive deficit after carotid angioplasty; and/or neonatal ischemia following hypothermic circulatory arrest.
  • methods are provided to treat patients with brain tumors, such as gliomas, by administering a compound selected according to the methods or processes described herein.
  • compounds selected according to the methods or processes described herein can be used prophylactically to prevent or protect against such diseases or neurological conditions, such as those described herein.
  • patients with a predisposition for an ischemic event such as a genetic predisposition
  • patients that exhibit vasospasms can be treated prophylactically with the methods and compounds described herein.
  • patients that have undergone cardiac bypass surgery can be treated prophylactically with the methods and compounds described herein.
  • methods are provided to treat patients with ischemic injury or hypoxia, or prevent or treat the neuronal toxicity associated with ischemic injury or hypoxia, by administering a compound selected according to the methods described herein.
  • neuropathic pain or related disorders are provided to treat patients with neuropathic pain or related disorders by administering a compound selected according to the methods or processes described herein.
  • the neuropathic pain or related disorder can be selected from the group including, but not limited to: peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndromes, peripheral neuropathies, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic low back pain, HIV neuropathic pain, trigeminal neuralgia, and/or central post-stroke pain.
  • Neuropathic pain can be associated with signals generated ectopically and often in the absence of ongoing noxious events by pathologic processes in the peripheral or central nervous system. This dysfunction can be associated with common syr allodynia, hyperalgesia, intermittent abnormal sensations, and spontaneous, burning, shooting, stabbing, paroxysmal or electrical-sensations, paresthesias, hyperpathia and/or dysesthesias, which can also be treated by the compounds and methods described herein.
  • the compounds and methods described herein can be used to treat neuropathic pain resulting from peripheral or central nervous system pathologic events, including, but not limited to trauma, ischemia; infections or from ongoing metabolic or toxic diseases, infections or endocrinologic disorders, including, but not limited to, diabetes mellitus, diabetic neurophathy, amyloidosis, amyloid polyneuropathy (primary and familial), neuropathies with monoclonal proteins, vasculitic neuropathy, HIV infection, herpes zoster—shingles and/or postherpetic neuralgia; neuropathy associated with Guillain-Barre syndrome; neuropathy associated with Fabry's disease; entrapment due to anatomic abnormalities; trigeminal and other CNS neuralgias; malignancies; inflammatory conditions or autoimmune disorders, including, but not limited to, demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome; and cryptogenic
  • neuropathic pain can be treated according to the methods and compositions described herein include, but are not limited to, exposure to toxins or drugs (such as aresnic, thallium, alcohol, vincristine, cisplatinum and dideoxynucleosides), dietary or absorption abnormalities, immuno-globulinemias, hereditary abnormalities and amputations (including mastectomy).
  • toxins or drugs such as aresnic, thallium, alcohol, vincristine, cisplatinum and dideoxynucleosides
  • dietary or absorption abnormalities such as aresnic, thallium, alcohol, vincristine, cisplatinum and dideoxynucleosides
  • immuno-globulinemias such as aresnic, thallium, alcohol, vincristine, cisplatinum and dideoxynucleosides
  • immuno-globulinemias such as aresnic, thallium, alcohol, vincristine, c
  • the compounds can also be used to treat the following diseases or neurological conditions, including, but not limited to: chronic nerve injury, chronic pain syndromes, such as, but not limited to ischemia following transient or permanent vessel occlusion, seizures, spreading depression, restless leg syndrome, hypocapnia, hypercapnia, diabetic ketoacidosis, fetal asphyxia, spinal cord injury, status epilepticus, concussion, migraine, hypocapnia, hyperventilation, lactic acidosis, fetal asphyxia during parturition, and/or retinopathies by administering a compound selected according to the methods or processes described herein.
  • chronic nerve injury chronic pain syndromes
  • chronic pain syndromes such as, but not limited to ischemia following transient or permanent vessel occlusion, seizures, spreading depression, restless leg syndrome, hypocapnia, hypercapnia, diabetic ketoacidosis, fetal asphyxia, spinal cord injury, status epilepticus, concussion, migraine, hypocapni
  • the use of the compounds of the invention reduces symptoms of neuropathic pain, stroke, traumatic brain injury, epilepsy, and other neurologic events or neurodegeneration resulting from NMDA receptor activation.
  • the methods involve administering t thereof an effective amount of a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, ester, or derivative thereof, or a pharmaceutical composition thereof.
  • Senile dementia of the Alzheimer's type is a debilitating neurodegenerative disease, mainly afflicting the elderly, characterized by a progressive intellectual and personality decline, as well as a loss of memory, perception, reasoning, orientation and judgment.
  • One feature of the disease is an observed decline in the function of cholinergic systems, and specifically, a severe depletion of cholinergic neurons (i.e., neurons that release acetylcholine, which is believed to be a neurotransmitter involved in learning and memory mechanisms). See, for example, Jones et al., Intern. J. Neurosci. 50:147 (1990); Perry, Br. Med. Bull. 42:63 (1986); and Sitaram et al., Science 201:274 (1978).
  • the NMDA receptors antagonists described herein are able to inhibit the prolonged influx of Ca 2+ ions which forms the basis of neuronal excitotoxicity.
  • the affinity and off-rate kinetics of the NMDA antagonists described herein may preserve some physiological function of the receptor so that it can still be activated by the relatively high concentrations of glutamate released following depolarization of the presynaptic neuron.
  • some NMDA receptor antagonists described here provide only partial block of the receptor even at concentrations that fully saturate the binding site.
  • Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors (see Rogawski and Wenk, “The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease,” CNS Drug Rev 9 (3): 275-308 (2003); and Robinson and Keating, “Memantine: a review of its use in Alzheimer's disease”. Drugs 66 (11): 1515-34 (2006). It has been proposed for use in treating Alzheimer's disease. Accordingly, it stands to reason that the instant compounds, which are NMDA antagonists, can similarly be used to treat Alzheimer's disease.
  • glutamate receptors are intimately involved in the molec cognition, learning and memory formation. Glutamate receptor modulators have been hypothesized to be capable of influencing cognition and memory formation. Thus, manipulation of the glutamate system by the subunit-selective antagonists described here could provide beneficial relief to patients suffering from Alzheimer's, other forms of dementia, as well as other neurological conditions that involve impaired judgment, memory, or cognition.
  • Parkinson's disease is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity. A feature of the disease appears to involve the progressive degeneration of dopaminergic neurons (i.e., which secrete dopamine).
  • dopaminergic neurons i.e., which secrete dopamine.
  • One symptom of the disease has been observed to be a concomitant loss of nicotinic receptors which are associated with such dopaminergic neurons, and which are believed to modulate the process of dopamine secretion. See Rinne et al., Brain Res. 547:167 (1991).
  • N-Methyl-D-aspartate (NMDA) glutamate receptors are a class of excitatory amino acid receptors, which have several important functions in the motor circuits of the basal ganglia, and are viewed as important targets for the development of new drugs to prevent or treat Parkinson's disease (PD).
  • NMDA receptors are ligand-gated ion channels composed of multiple subunits, each of which has distinct cellular and regional patterns of expression. They have complex regulatory properties, with both agonist and co-agonist binding sites and regulation by phosphorylation and protein-protein interactions. They are found in all of the structures of the basal ganglia, although the subunit composition in the various structures is different.
  • NMDA receptors present in the striatum are crucial for dopamine-glutamate interactions. The abundance, structure, and function of striatal receptors are altered by the dopamine depletion and further modified by the pharmacological treatments used in PD.
  • NMDA receptor antagonists are effective anti-parkinsonian agents and can reduce the complications of chronic dopaminergic therapy (wearing off and dyskinesias).
  • Use of these agents in humans has been limited because of the adverse effects associated with nonselective blockade of NMDA receptor function, but the development of more potent and subunit-selective pharmaceuticals holds the promise of an important new therapeutic approach for PD. Hallett and Standaert, “Rationale for and use of NMDA receptor antagonists in Parkinson's disease,” Pharmacology & Therapeutics, vol. 102, no 2, pp. 155-174 (2004).
  • NR2D blockade may improve parkinsonian symptoms.
  • anticholinergic drugs are used to treat striatal cholinergic dysfunction in Parkinson's patients. Whereas activation of NMDA receptors can enhance striatal acetylcholine release, blockade of NR2D-containing receptors should mimic the effect of anticholinergic drugs by reducing cholinergic interneuron excitability, and decreasing acetylcholine release.
  • the invention relates to a method of treating tardive dyskinesia in humans.
  • the invention reduces involuntary movements or hyperkinesia characteristic of patients with tardive movement disorders, including tardive dyskinesia, by administering an NMDA receptor antagonist as defined herein.
  • the NMDA receptor antagonists can also be used to treat other motor disorders ranging from resting tremor to various dyskinesias.
  • the NR2C subunit is abundantly expressed in the cerebellum, a structure that is involved in fine motor coordination. Thus, the compounds described here that act on the NR2C subunit could enhance motor function in a beneficial way for a large number of patients.
  • the compounds described here that alter the NR2C and NR2D subunit activity could be beneficial in facilitating rehabilitation after brain injury of any type. Such compounds might enhance motor reprogramming during physical therapy, thereby increasing functionality and speeding recovery.
  • the compounds selected or identified according to the processes and methods described herein generally avoid substantial side effects associated with other classes of NMDA receptor antagonists.
  • such compounds do not substantially exhibit the side effects associated with NMDA antagonists of the glutam Selfotel, D-CPPene (SDZ EAA 494) and AR-R15896AR (ARL 15896AR), including, agitation, hallucination, confusion and stupor (Davis et al. (2000) Stroke 31(2):347-354; Diener et al. (2002), J Neurol 249(5):561-568); paranoia and delirium (Grotta et al.
  • such compounds do not exhibit the side effects associated with NMDA antagonists of the glycine site, such as HA-966, L-701,324, D-cycloserine, CGP-40116, and ACEA 1021, including significant memory impairment and motor impairment (Wlaz, P (1998), Brain Res Bull 46(6):535-540).
  • such compounds do not exhibit the side effects of NMDA high affinity receptor channel blockers, such as MK-801, phencyclidine (PCP), and ketamine, including, psychosis-like effects (Hoffman, D C (1992), J Neural Transm Gen Sect 89:1-10); cognitive deficits (decrements in free recall, recognition memory, and attention; Malhotra et al (1996), Neuropsychopharmacology 14:301-307); schizophrenia-like symptoms (Krystal et al (1994), Arch Gen Psychiatry 51:199-214; Lahti et al. (2001), Neuropsychopharmacology 25:455-467), and hyperactivity and increased stereotopy (Ford et al (1989) Physiology and behavior 46: 755-758.
  • NMDA high affinity receptor channel blockers such as MK-801, phencyclidine (PCP), and ketamine
  • motor impairment can be measured by, for example, measuring locomotor activity and/or rotorod performance.
  • Rotorod experiments involve measuring the duration that an animal can remain on an acceleratin embodiment
  • memory impairment can be assessed, for example, by using a passive avoidance paradigm; Sternberg memory scanning and paired words for short-term memory, or delayed free recall of pictures for long-term memory.
  • anxiolytic-like effects can be measured, for example, in the elevated plus maze task.
  • cardiac function can be monitored, blood pressure and/or body temperature measured and/or electrocardiograms conducted to test for side effects.
  • Antagonists of the NMDA receptor i.e., compounds which reduce the current flow through the channel, are required to inhibit the development of tolerance and dependence.
  • inhibiting nitric oxide synthase which is biochemically equivalent to reducing cation flux through the NMDA receptor with an antagonist, also inhibits dependence.
  • the compounds can be used along with opiates to manage chronic pain in severely ill patients and alleviate the pain of withdrawal both in legitimate and illegitimate drug users.
  • Bone formation refers to the creation of new bone mass. This includes the process whereby new bone structure grows or the density of existing bone is increased. Osteoblasts form bone by producing extracellular organic matrix, or osteoid and then mineralizing the matrix to form bone.
  • the main mineral component of bone is crystalline hydroxyapetite, which comprises much of the mass of normal adult bone.
  • the mammal is a human in need of enhanced bone formation.
  • the human in need has a bone deficit, which means that they will have less bone than desirable or that the bone will be less dense or strong than desired.
  • a bone deficit may be localized, such as that caused by a bone fracture or systemic, such as that caused by osteoporosis. Bone deficits may result from a bone remodeling disorder whereby the balance between bone formation and bone resorption is shifted, resulting in a bone deficit.
  • Bone remodeling disorders include osteoporosis, Paget's disease, osteoarthritis, rheumatoid arthritis, achondroplasia, osteochodrytis, hyperparathyroidism, osteogenesis imperfecta, congenital hypophosphatasia, fribromatous lesions, fibrous displasia, multiple myeloma, abnormal bone turnover, osteolytic bone disease and periodontal disease.
  • Bone remodeling disorders includes metabolic bone diseases which are characterized by disturbances in the organic matrix, bone mineralization, bone remodeling, endocrine, nutritional and other factors which regulate skeletal and mineral homeostasis. Such disorders may be hereditary or acquired and generally are systemic affecting the entire skeletal system.
  • bone diseases may be treated in accordance with the present invention, for example all those bone diseases connected with the bone-remodeling cycle.
  • diseases include all forms osteomalacia, rickets and Paget's disease.
  • Osteoporosis especially of the post-menopausal, male and steroid-induced types, is of particular note.
  • the compounds can be used as antiresorption agents generally, as bone promotion agents and as anabolic bone agents. Such uses form another aspect of the present invention.
  • the bone deficit may be attributed to excess bone resorption by differentiated osteoclasts.
  • the methods and compositions of the invention may be employed to inhibit osteoclast differentiation, thus inhibiting bone resorption.
  • the lanthanum compound may be administered simultaneously or sequentially with other active ingredients.
  • active ingredients may, for example include other medicaments or compositions capable of interacting with the bone remodeling cycle and/or which are of use in fracture repair.
  • medicaments or compositions may, for example, be those of use in the treatment of osteoarthritis or osteoporosis.
  • Bone enhancing agents known in the art to increase bone formation, bone density or bone mineralization, or to prevent bone resorption may be used in the methods and pharmaceutical compositions of the invention.
  • Suitable bone enhancing agents include natural or synthetic hormones, such as estrogens, androgens, calcitonin, prostaglandins and parathormone; growth factors, such as platelet-derived growth factor, insulin-like growth factor, transforming growth factor, epidermal growth factor, connective tissue growth factor and fibroblast growth factor; vitamins, particularly vitamin D; minerals, such as calcium, aluminum, strontium and fluoride; statin drugs, including pravastatin, fluvastatin, simvastatin, lovastatin and atorvastatin; agonists or antagonist of receptors on the surface of osteoblasts and osteoclasts, including parathormone receptors, estrogen receptors and prostaglandin receptors; bisphosphonate and anabolic bone agents.
  • hormones such as estrogens, androgens, calcitonin, prostag
  • High throughput screening is a recent technology that has been developed primarily within the pharmaceutical industry. It has emerged in response to the profusion of new biological targets and the need of the pharmaceutical industry to generate novel drugs rapidly in a changed commercial environment. Its development has been aided by the invention of new instrumentation, by new assay procedures, and by the availability of databases that allow huge numbers of data points to be managed effectively. High throughput scr with combinatorial chemistry, rational design, and automation of laboratory procedures has led to a significantly accelerated drug discovery process compared to the traditional one-compound-at-a-time approach. Screens may be performed manually. However robotic screening of the compound libraries is preferred as a time- and labor-saving device.
  • the present invention also relates to a high throughput bioassay to identify antagonists that are selective for NR2C- or NR2D-containing receptors.
  • High throughput screening typically involves lead generation, followed by lead optimization.
  • NR2C/D-containing recombinant NMDA receptors show little desensitization and are Ca +2 permeable—two properties that renders them amenable to optical assays that measure agonist-induced Ca +2 accumulation in mammalian cells using multi-well formats.
  • the assay involves using a cell line that expresses the NR1 subunit together with either NR2C or NR2D.
  • These cell lines can be prepared by transfecting a cell line with an appropriate vector that includes the DNA encoding the NR2C or NR2D receptors.
  • One suitable cell line is BHK-1 (Syrian hamster kidney BHK-21 is a subclone (clone 13) of the parental line established from the kidneys of five unsexed, one-day-old hamsters in 1961).
  • the NR2D receptor cDNA has also been cloned, for example, in 293T cells (Glover et al., “Interaction of the N-Methyl-D-Aspartic Acid Receptor NR2D Subunit with the c-Abl Tyrosine Kinase*,” J. Biol. Chem., Vol. 275, Issue 17, 12725-12729, April cDNA for NR2D is also described in this reference.
  • NR2D cDNA (clone designation pNR2D422) is also disclosed in Arvanian, et al., “Viral Delivery of NR2D Subunits Reduces Mg2+ Block of NMDA Receptor and Restores NT-3-Induced Potentiation of AMPA-Kainate Responses in Maturing Rat Motoneurons,” J Neurophysiol 92: 2394-2404, 2004.
  • Lin et al. describe several overlapping cDNA clones containing 3995 nucleotides of the human 2C NMDA receptor subunit (NR2C) that were isolated from human hippocampal and cerebellar cDNA libraries. The predicted protein sequence is 1233 amino acids long. Lin et al.
  • NR2C neurotrophic factor
  • hippocampus amygdala
  • caudate nucleus caudate nucleus
  • corpus callosum subthalamic nuclei and thalamus
  • pancreas demonstrating a widespread expression pattern of the NR2C gene, both in the CNS and in the periphery.
  • the high throughput bioassay uses commercially-available BHK-21 cell lines expressing NR1 under control of the Tet-On system (Clontech) (Hansen et al 2008), and which constitutively express either NR2C or NR2D.
  • FIG. 5A illustrates vector design for the NR2D cell line.
  • a similar strategy can be used for the NR2C cell line, except that the NR2C cDNA is used in place of NR2D cDNA.
  • NMDA receptor subunits Stable expression of NMDA receptor subunits is cytotoxic.
  • the culture media can be supplemented with NMDA receptor antagonists, for example, DL-APV and 7Cl-kynurenate.
  • Functional NR1 expression can be induced by doxycyclin before the assay.
  • Fura-2 Ca +2 imaging of the functional response of the NR1/NR2D cell line can be used to produce a glutamate EC 50 value, which can be compared to that measured from two-electrode voltage-clamp assay. If these values are comparable, this suggests that the cell line faithfully reproduces NR1/NR2D properties.
  • a cell line such as a BHK cell line which expresses a low affinity glutamate transporter system (K m ⁇ 40 ⁇ M) should help keep glutamate concentration low, and reduce cytotoxicity due to NMDA receptor over-activation (Scott & Pateman, 1978; Arathoon & Telling, 1981).
  • K m ⁇ 40 ⁇ M low affinity glutamate transporter system
  • BHK cells can be preferred, because they adhere tightly to the allowing thorough washing of antagonists present during culture without losing cells from the bottom of the dish.
  • BHK cells can extrude a low level of glutamate through the reversal of the transporter when glutamate is absent from the extracellular solution, such as during wash and dye loading. Because glutamate activates NR2D-containing receptors with submicromolar EC 50 ( ⁇ 500 nM), even tens of nanomolar concentrations of glutamate (plus trace glycine) extruded by BHK cells from time of washing through dye loading are sufficient to activate NR1/NR2D receptors, injure cells, and compromise subsequent assays. This toxic activation also creates a high baseline Ca +2 signal, which compromises the signal to noise ratio.
  • a competitive glycine site antagonist such as 7-Cl-kynurenate
  • Use of a relatively low affinity antagonist enhances cell health during dye loading and experimental setup by preventing continual NR1/NR2D receptor activation by low levels of glutamate extruded by BHK cells.
  • the competitive glycine site antagonist is easily displaced by addition of an excess of glycine (for example, around 1 mM) together with glutamate (around 100 ⁇ M).
  • an excess of glycine for example, around 1 mM
  • glutamate around 100 ⁇ M
  • the presence of antagonist improves the reliability and the signal-to-noise ratio for the assay.
  • Z′ values are a standard measure of variability for multi-well assays, with values above 0.5 considered a good indication that an assay is suitable for single well screening of test compounds (Zhang et al. 1999).
  • Real time Ca +2 signals can be recorded in multi-well plates, for example, 96 well plates, using plate readers, for example, FlexStation II multi-mode plate readers.
  • the assay has been designed to identify non-competitive antagonists of NR2D-containing receptors by using supramaximal concentrations of glutamate and glycine, which decreases the likelihood that competitive antagonists will be identified.
  • the assay can be validated using commercially available libraries, s library (1200 compounds), which contain a number of known NMDA receptor antagonists.
  • Test compounds can be added to each well, together with agonist, to yield a final well concentration of around 10 ⁇ M test compound in 0.9% DMSO.
  • Compounds that alter the response of any well, compared to on-plate control wells, beyond 2.5-fold of the standard deviation (calculated from all wells on the plate) and by more than 40% of the control response on a given plate, can be selected for secondary screening. This secondary screening can be performed, for example, using two-electrode voltage-clamp recordings from Xenopus oocytes expressing recombinant NR1/NR2D receptors.
  • Further screening can also include using a competitive binding assay, which preferably is characterized by co-incubation of putative leads with known NMDA antagonists.
  • the library of candidate compounds is a focused library of candidate compounds, for lead optimization, based on the structure of high affinity leads identified in a first lead generation assay.
  • the library of candidate compounds can be a combinatorial library of, for example, drug-like molecules or a focused small molecule library.
  • the invention also provides compounds, including small molecules and peptides, proteins, and genetic material, identified according to the methods described above, as well as methods of treating patients in need of a subtype specific NMDA modulator, which methods involve administering the modulator to a patient in need of treatment thereof.
  • Small molecules to be screened are advantageously collected in the form of a combinatorial library.
  • libraries of drug-like small molecules such as beta-turn mimetic libraries and the like, may be purchased from, for example, ChemDiv, Pharmacopia or Combichem or synthesized and are described in Tietze and Lieb, Curr. Opin. Chem. Biol. 2:363-371, 1998; Carrell et al., Chem Biol. 2:171-183, 1995; U.S. Pat. No. 5,880,972, U.S. Pat. No. 6,087,186 and U.S. Pat. No. 6,184,223, the disclosures of which are hereby incorporated by reference.
  • any of these libraries known in the art are suitable for screening, as are random libraries or individual compounds.
  • hydrophilic compounds are preferred because they are more easily soluble, more easily synthesized, and more easily compounded.
  • Compounds having an average molecular weight of about 500 often are most useful, however, compounds outside this range, or even far outside this range also may be used.
  • compounds having c logP scores of about 5.0 are preferred.
  • Simple filters like Lipinski's “rule of five” have and may be used to improve the quality of leads discovered by this inventive strategy by using only those small molecules which are bioavailable. See Lipinski et al., Adv. Drug Delivery Rev. 23:3-25, 1997.
  • Combinatorial chemistry small molecule “libraries” can be screened against drug targets. The idea is that diversity of chemical structures increases the chances of finding the needle in the 10 200 possible small organic molecule haystack. These collections provide an excellent source of novel, readily available leads. For example, ChemDiv uses more than 800 individual chemical cores, a unique Building Block Library, and proprietary chemistry in designing its Diversity Collections (small molecule libraries) to assemble 80,000-100,000 compounds a year. CombiLab lead library sets of 200-400 compounds also can be produced as a follow-up.
  • ChemDiv's compounds are designed to ensure their similarity to drugs adjusted according to proprietary algorithms of “drug-likeness definitions” (group similarity and advanced neural net approaches), and a variety of intelligent instruments for ADME&T (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties prediction, such as partition coefficient, solubility, dissociation coefficients, and acute toxicity.
  • ADME&T Absorption, Distribution, Metabolism, Excretion and Toxicity
  • a library of compounds is selected that are predicted to be “drug-like” based on properties such as pKa, log P, size, hydrogen bonding and polarity.
  • the inventive multi-step approach which yields high affinity peptides in the first step, and small molecules in a subsequent step reduces the number of artificial hits by eliminating the lower affinity small molecules that would be selected and have to be assayed in a normal high throughput screening method.
  • it focuses the search for molecules that can modulate the binding of a peptide that mimics the G protein rather than screening for binding to any site on the receptor.
  • Other advantages of this technology are that it is simple to implement, amenable to many different classes of receptors, and capable of rapidly screening very large libraries of compounds.
  • Peptides desirably are screened using a pooled approach because of the layer members of peptides which are screened in the first instance. Peptides may be screened individually as well, but preferably are screened in pools of about 10 4 -10 12 peptides per well or about 10 8 -10 10 peptide per well.
  • the most strongly binding and effective compounds are subjected to a subsequent lead optimization screening step.
  • Databases can be used to store and manipulate data on the compounds obtained using the screen, and can compare the binding affinity against the NR2C and NR2D receptors, and/or other receptors, to determine the selectivity of the compounds for the desired receptor.
  • Fura-2 Ca 2+ imaging of the functional response of the NR1/NR2D cell line produced a glutamate EC 50 value (340 nM) that was similar to that measured from two-electrode voltage-clamp assay (460 nM), suggesting this cell line faithfully reproduces NR1/NR2D properties.
  • the BHK cell line expresses a low affinity glutamate transporter system (K M ⁇ 40 ⁇ M) which should help keep glutamate concentration low and reduce cytotoxicity due to NMDA receptor over-activation (Scott & Pateman, 1978; Arathoon & Telling, 1981). In addition, these cells adhere tightly to the culture plastic, allowing thorough washing of antagonists present during culture without losing cells from the bottom of the dish. However, BHK cells can extrude a low level of glutamate through the reversal of the transporter when glutamate is absent from the extracellular solution, such as during wash and dye loading.
  • K M ⁇ 40 ⁇ M low affinity glutamate transporter system
  • glutamate activates NR2D-containing receptors with submicromolar EC 50 ( ⁇ 500 nM), even tens of nanomolar concentrations of glutamate (plus trace glycine) extruded by BHK cells from time of washing through dye loading are sufficient to activate NR1/NR2D receptors, injure cells, and compromise subsequent assays.
  • This tonic activation also creates a high baseline Ca 2+ signal, which compromises the signal to noise ratio.
  • cRNA was synthesized from linearized template cDNA for rat glutamate receptor subunits according to manufacturer specifications (Ambion). Quality of synthesized cRNA was assessed by gel electrophoresis, and quantity was estimated by spectroscopy and gel electrophoresis. Stage V and VI oocytes were surgically removed from the ovaries of large, well-fed and healthy Xenopus laevis anesthetized with 3-amino-benzoic acid ethyl ester (3 gm/l) as previously described.
  • Clusters of isolated oocytes were incubated with 292 U/ml Worthington (Freehold, N.J.) type IV collagenase or 1.3 mg/ml collagenase (Life Technologies, Gaithersburg, MD; 17018-029) for 2 hr in Ca 2+ -free solution comprised of (in mM) 115 NaCl, 2.5 KCl, and 10 HEPES, pH 7.5, with slow agitation to remove the follicular cell layer.
  • Oocytes were then washed extensively in the same solution supplemented with 1.8 mM CaCl 2 and maintained in Barth's solution comprised of (in mM): 88 NaCl, 1 KCl, 2.4 NaHCO 3 , 10 HEPES, 0.82 MgSO 4 , 0.33 Ca(NO 3 ) 2 , and 0.91 CaCl 2 and supplemented with 100 ⁇ g/m1 gentamycin, 10 ⁇ g/ml streptomycin, and 10 ⁇ g/ml penicillin.
  • Oocytes were manually defolliculated and injected within 24 hrs of isolation with 3-5 ng of NR1 subunit cRNA and 7-10 ng of NR2 cRNA subunit in a 50 nl volume, or 5-10 ng of AMPA or kainate receptor cRNAs in a 50 nl volume, and incubated in Barth's solution at 18° C. for 1-7 d.
  • Glass injection pipettes had tip sizes ranging from 10-20 microns, and were backfilled with mineral oil.
  • Two electrode voltage-clamp recordings were made 2-7 days post-injection as previously described.
  • Oocytes were placed in a dual-track plexi-glass recording chamber with a single perfusion line that splits in a Y-configuration to perfuse two oocytes.
  • Dual recordings were made at room temperature (23° C.) using two Warner OC725B two-electrode voltage clamp amplifiers, arranged as recommended by the manufacturer.
  • Glass microelectrodes (1-10 Megaohms) were filled with 300 mM KCl (voltage electrode) or 3 M KCl (current electrode).
  • the bath clamps communicated across silver chloride wires placed into each side of the recording chamber, both of which were assumed to be at a reference potential of 0 mV.
  • Oocytes were perfused with a solution comprised of (in mM) 90 NaCl, 1 KCl, 10 HEPES, and 0.5 BaCl 2 ; pH was adjusted by addition of 1-3 M NaOH of HC1 to 7.4. Oocytes were recorded under voltage clamp at ⁇ 40 mV. Final concentrations for control application of glutamate (100 ⁇ M) plus glycine (30 ⁇ M) were achieved by adding appropriate volumes from 100 or 30 mM stock solutions, respectively. In some experiments, 10 ⁇ M EDTA was obtained by adding a 1:1000 dilution of 10 mM EDTA, in order to chelate contaminant divalent ions such as Zn 2+ .
  • Concentration-response curves for experimental compounds were obtained by applying in successive fashion maximal glutamate/glycine, followed by glutamate/glycine plus variable concentrations of experimental compounds. Concentration effect curves consisting of 4 to 8 concentrations were obtained in this manner. The baseline leak current at ⁇ 40 mV was measured before and after recording, and the full recording linearly corrected for any change in leak current. Oocytes with glutamate-evoked responses smaller than 50 nA were not included in the analysis. The level of inhibition by applied experimental compounds was expressed as a percent of the initial glutamate response, and averaged together across oocytes from a single frog. Each experiment consisted of recordings from 3 to 10 oocytes obtained from a single frog. Results from multiple experiments were pooled, and the average percent responses at antagonist concentrations were fitted by the equation,
  • minimum is the residual percent response in saturating concentration of the experimental compounds
  • IC 50 is the concentration of antagonist that causes half of the achievable inhibition
  • nH is a slope factor describing steepness of the inhibition curve.
  • Minimum was constrained to be greater than or equal to 0.
  • Compounds can be evaluated for binding to the human ether-a-go-go potassium channel (hERG) expressed in HEK293 cells by displacement of 3 [II]-astemizole according to the methods by Finlayson et al. (K. Finlayson., L. Turnbull, C. T. January, J. Sharkey, J. S. Kelly; [ 3 H]Dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. Eur. J. Pharmacol. 2001, 430, 147-148). Compounds can be incubated at 1 or 10 ⁇ M final concentration, in duplicate, and the amount of displaced 3 [H]-astemizole determined by liquid scintillation spectroscopy.
  • a seven concentration (each concentration in duplicate) displacement curve can be generated to determine an IC 50 .
  • Binding to the rat alpha-1 adrenergic receptor in rat brain membranes can be determined by displacement of 3 [H]-prazosin (P. Greengrass and R. Bremner; Binding characteristics of 3 H-prazosin to rat brain a-adrenergic receptors. Eur. J. Pharmacol. 1979, 55: 323-326).
  • Compounds can be incubated at 0.3 or 3 ⁇ M final concentration, in duplicate, and the amount of displaced 3 [H]-prazosin determined by liquid scintillation spectroscopy.
  • Binding IC 50 values can be determined from displacement curves (four-six concentrations, each concentration in duplicate) fit by a non-linear, least squares, regression analysis using MathIQ (ID Business Solutions Ltd., UK).
  • the binding Ki's can be determined from the IC 50 according to the method of Cheng and Prusoff (Y. Cheng and W. H. Prusoff; Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 percent inhibition (IC 50 ) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22: 3099-3108).
  • Compounds can be incubated with pooled human (from at least 10 donors) or rat liver microsomes, 1.0 mg/ml microsomal protein, and 1 mM NADPH, in buffer at 37° C. in a shaking water bath according to the method of Clarke and Jeffrey (S. E. Clarke and P. Jeffrey; Utility of metabolic stability screening: comparison of in vitro and in vivo clearance. Xenobiotica 2001. 31: 591-598).
  • the samples can be extracted and analyzed for the presence of the parent compound by LC-MS/MS. The parent material remaining in the sample at 60 min can be compared to that at 0 min and expressed as a percentage.
  • a control compound, testosterone can be run in parallel.
  • K-EDTA anticoagulant
  • Brain tissue can be weighed, homogenized on ice in 50 mM phosphate buffer (2 ml per brain) and the homogenate stored at ⁇ 80 ° C.
  • Plasma and brain homogenate samples can be extracted by the addition of 5 volumes of cold acetonitrile, mixed well by vortexing and centrifuged at 4000 rpm for 15 minutes.
  • the supernatant fractions can be analyzed by LC-MS/MS operating in multiple reaction monitoring mode (MRM).
  • MRM multiple reaction monitoring mode
  • the amount of parent compound in each sample can be calculated by comparing the response of the analyte in the sample to that of a standard curve.
  • a high throughput bioassay was developed to identify antagonists that are selective for NR2C- or NR2D-containing receptors.
  • NR2C- or NR2D-containing recombinant NMDA receptors show little desensitization and are Ca +2 permeable—two properties that renders them amenable to optical assays that measure agonist-induced Ca +2 accumulation in mammalian cells using multi-well formats.
  • the high throughput bioassay used a commercially-available BHK-21 cell line expressing NR1 under control of the Tet-On system (Clontech) (Hansen et al 2008) to create two new cell lines that constitutively express either NR2C or NR2D.
  • FIG. 5A illustrates vector design for the NR2D cell line.
  • a similar strategy was employed for the NR2C cell line, except that the NR2C cDNA replaced the NR2D cDNA.
  • NMDA receptor subunits Stable expression of NMDA receptor subunits is cytotoxic. To avoid this toxicity, the culture media was supplemented with NMDA receptor antagonists (200 ⁇ M DL-APV and 200 ⁇ M 7C1-kynurenate), and functional NR1 expression was induced by doxycyclin 48 hours prior to assay ( FIG. 5B ). Fura-2 Ca +2 imaging of the functional response of the NR1/NR2D cell line ( FIG. 5C ) produced a glutamate EC 50 value (340 nM) that was similar to that measured from two-electrode voltage-clamp assay (460 nM), suggesting this cell line faithfully reproduces NR1/NR2D properties.
  • the BHK cell line expresses a low affinity glutamate transporter system (K m ⁇ 40 ⁇ M) which should help keep glutamate concentration low and reduce cytotoxicity due to NMDA receptor over-activation (Scott & Pateman, 1978; Arathoon & Telling, 1981).
  • K m ⁇ 40 ⁇ M low affinity glutamate transporter system
  • BHK cells can extrude a low level of glutamate through the reversal of the transporter when glutamate is absent from the extracellular solution, such as during wash and dye loading.
  • glutamate activates NR2D-containing receptors with submicromolar EC 50 ( ⁇ 500 nM), even tens of nanomolar concentrations of glutamate (plus trace glycine) extruded by BHK cells from the time of washing through dye loading are sufficient to activate NR1/NR2D receptors, injure cells, and compromise subsequent assays. This toxic activation also creates a high baseline Ca +2 signal, which compromises the signal to noise ratio.
  • Z′ values are a standard measure of variability for multi-well assays, with values above 0.5 considered a good indication that an assay is suitable for single well screening of test compounds (Zhang et al. 1999).
  • FIG. 6 shows data from one plate testing compounds from our biaryl focused library.
  • This plate contained a novel inhibitor (compound 529) that we had previously identified (unpublished data).
  • the potentiation of the signal by compound 237 confirms that the activation of NRI/NR2D by maximally effective concentrations of agonists do not saturate Fluo-4 (Kd 350 nM).
  • This test screen of NRI/NR2D expressing BHK cells successfully identified the following known NMDA receptor antagonists in the Lopac/focused library; (+)MK-801, ( ⁇ )MK-801, memantine, ifenprodil, CNS-1102 (aptiganel), dextrorphan, levallorphan, and N-allylnormetazoline.
  • An NR1/NR2C expressing cell line was made using similar methods, optimized for single well screening, and tested for sensitivity to known NMDA antagonists. The results obtained confirmed that the NR1/NR2C cell line was also well-suited for high-throughput screening

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US10273214B2 (en) 2019-04-30
US20140275529A1 (en) 2014-09-18
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US8822462B2 (en) 2014-09-02
WO2010088414A2 (fr) 2010-08-05
US20120028977A1 (en) 2012-02-02
WO2010088414A3 (fr) 2011-03-31

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