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WO1998056752A1 - Composes actifs sur un nouveau site des canaux calciques actives par les recepteurs servant au tratitement des troubles et des maladies neurologiques - Google Patents

Composes actifs sur un nouveau site des canaux calciques actives par les recepteurs servant au tratitement des troubles et des maladies neurologiques Download PDF

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WO1998056752A1
WO1998056752A1 PCT/US1998/011608 US9811608W WO9856752A1 WO 1998056752 A1 WO1998056752 A1 WO 1998056752A1 US 9811608 W US9811608 W US 9811608W WO 9856752 A1 WO9856752 A1 WO 9856752A1
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receptor
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Alan L. Mueller
Scott T. Moe
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Shire NPS Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
    • C07C211/32—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings containing dibenzocycloheptane or dibenzocycloheptene ring systems or condensed derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/90—Xanthenes with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/20—Thioxanthenes with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9

Definitions

  • This invention relates to compounds useful as neuroprotectants, anticonvulsants, anxiolytics, analgesics, muscle relaxants or adjuvants to general anesthetics.
  • the invention relates as well to methods useful for the treatment of neurological disorders and diseases, including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy, anxiety, and neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) .
  • neurological disorders and diseases including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy, anxiety, and neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS
  • the invention relates as well to methods of screening for compounds active at a novel site on receptor-operated calcium channels, and thereby possessing therapeutic utility as neuroprotectants, anticonvulsants, anxiolytics, analgesics, muscle relaxants or adjuvants to general anesthetics, and/or possessing potential therapeutic utility for the treatment of neurological disorders and diseases as described above.
  • Glutamate is the major excitatory neurotransmitter in the mammalian brain. Glutamate binds or interacts with one or more glutamate receptors which can be differentiated pharmacologically into several subtypes. In the mammalian central nervous system (CNS) there are three main subtypes of ionotropic glutamate receptors, defined pharmacologically by the selective agonists N-methyl-D-aspartate (NMDA) , kainate (KA) , and o.-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA) .
  • NMDA N-methyl-D-aspartate
  • KA kainate
  • AMPA o.-amino-3-hydroxy-5-methylisoxazole-4- propionic acid
  • the NMDA receptor has been implicated in a variety of neurological pathologies including stroke, head trauma, spinal cord injury, epilepsy, anxiety, and neurodegenerative diseases such as Alzheimer's Disease (Watkins and Collingridge, The NMDA Receptor, Oxford: IRL Press, 1989) .
  • a role for NMDA receptors in nociception and analgesia has been postulated as well
  • AMPA receptors have been widely studied for their possible contributions to such neurological pathologies (Fisher and Bogousslavsky, Evolving toward effective therapy for acute ischemic stroke. J. Amer. Med. Assoc. 270: 360, 1993; Yamaguchi et al . , Anticonvulsant activity of AMPA/kainate antagonists: Comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant seizure models. Epilepsy Res . 15: 179, 1993) .
  • the NMDA receptor When activated by glutamate, the endogenous neurotransmitter, the NMDA receptor permits the influx of extracellular calcium (Ca 2+ ) and sodium (Na + ) through an associated ion channel.
  • the NMDA receptor allows considerably more influx of Ca 2+ than do kainate or AMPA receptors (but see below) , and is an example of a receptor- operated Ca 2+ channel. Normally, the channel is opened only briefly, allowing a localized and transient increase in the concentration of intracellular Ca 2+ ([Ca 2+ ] i ), which, in turn, alters the functional activity of the cell.
  • the activity of the NMDA receptor-ionophore complex is regulated by a variety of modulatory sites that can be targeted by selective antagonists.
  • Competitive antagonists such as the phosphonate AP5
  • noncompetitive antagonists such as phencyclidine (PCP) , MK-801 or magnesium (Mg 2+ )
  • PCP phencyclidine
  • MK-801 or magnesium (Mg 2+ ) act within the associated ion channel (ionophore)
  • glycine acts as a co-agonist, so that both glutamate and glycine are necessary to fully elicit NMDA receptor-mediated responses.
  • NMDA receptor function Other potential sites for modulation of NMDA receptor function include a zinc (Zn 2+ ) binding site and a sigma ligand binding site. Additionally, endogenous polyamines such as spermine are believed to bind to a specific site and so potentiate NMDA receptor function (Ransom and Stec, Cooperative modulation of [ 3 H]MK-801 binding to the NMDA receptor-ion channel complex by glutamate, glycine and polyamines. J. Neurochem. 51: 830, 1988) .
  • the potentiating effect of polyamines on NMDA receptor function may be mediated via a specific receptor site for polyamines; polyamines demonstrating agonist, antagonist, and inverse agonist activity have been described (Reynolds, Arcaine is a competitive antagonist of the polyamine site on the NMDA receptor. Europ. J. Pharmacol . 177: 215, 1990; Williams et al . , Characterization of polyamines having agonist, antagonist, and inverse agonist effects at the polyamine recognition site of the NMDA receptor. Neuron 5: 199, 1990) .
  • Radioligand binding studies have demonstrated additionally that higher concentrations of polyamines inhibit NMDA receptor function (Reynolds and Miller, Ifenprodil is a novel type of NMDA receptor antagonist: Interaction with polyamines. Molec. Pharmacol . 36: 758, 1989; Williams et al . , Effects of polyamines on the binding of [ 3 H]MK-801 to the NMDA receptor: Pharmacological evidence for the existence of a polyamine recognition site. Molec. Pharmacol . 36: 575, 1989; Sacaan and Johnson, Characterization of the stimulatory and inhibitory effects of polyamines on [ 3 H]TCP binding to the NMDA receptor-ionophore complex. Molec. Pharmacol .
  • NMDARl NMDA receptor subunits
  • NMDAR2A NMDAR2A
  • NMDAR2D NMDAR2D
  • alternative splicing gives rise to at least six additional isoforms. It appears that NMDARl is a necessary subunit, and that combination of NMDARl with different members of NMDAR2 forms the fully functional NMDA receptor-ionophore complex.
  • the NMDA receptor-ionophore complex thus, can be defined as a hetero-oligomeric structure composed of at least NMDARl and NMDAR2 subunits; the existence of additional, as yet undiscovered, subunits is not excluded by this definition.
  • NMDARl has been shown to possess binding sites for glutamate, glycine, Mg 2+ , MK-801, and Zn 2+ .
  • AMPA receptors designated GluRl, GluR2, GluR3, and GluR4 (also termed GluRA through GluRD) , each of which exists in one of two forms, termed flip and flop, which arise by RNA alternative splicing.
  • GluRl, GluR3 and GluR4 when expressed as homomeric or heteromeric receptors, are permeable to Ca 2+ , and are therefore examples of receptor- operated Ca 2+ channels.
  • Expression of GluR2 alone or in combination with the other subunits gives rise to a receptor which is largely impermeable to Ca 2+ .
  • most native AMPA receptors studied in si tu are not Ca 2+ -permeable (discussed above) , it is believed that such receptors in situ possess at least one GluR2 subunit.
  • the GluR2 subunit is functionally distinct by virtue of the fact that it contains an arginine residue within the putative pore- forming transmembrane region II; GluRl, GluR3 and GluR4 all contain a glutamine residue in this critical region (termed the Q/R site, where Q and R are the single letter designations for glutamine and arginine, respectively) .
  • the activity of the AMPA receptor is regulated by a number of modulatory sites that can be targeted by selective antagonists (Honore et al . , Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists.
  • NMDA receptor Compounds that act as competitive or noncompetitive antagonists at the NMDA receptor are said to be effective in preventing neuronal cell death in various in vitro neurotoxicity assays (Meldrum and Garthwaite, Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol . Sci . 11: 379, 1990) and in in vivo models of stroke (Scatton, Therapeutic potential of NMDA receptor antagonists in ischemic cerebrovascular disease in Drug Strategies in the Prevention and Treatment of Stroke, IBC Technical Services Ltd., 1990). Such compounds are also effective anticonvulsants (Meldrum, Excitatory amino acid neurotransmission in epilepsy and anticonvulsant therapy in Excitatory Amino Acids .
  • AMPA receptor antagonists have been shown to possess neuroprotectant (Fisher and Bogousslavsky, Evolving toward effective therapy for acute ischemic stroke. J. Amer. Med. Assoc. 270: 360, 1993) and anticonvulsant (Yamaguchi et al . , Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant seizure models. Epilepsy Res . 15: 179, 1993) activity in animal models of ischemic stroke and epilepsy, respectively.
  • the nicotinic cholinergic receptor present in the mammalian CNS is another example of a receptor-operated Ca 2+ channel (Deneris et al . , Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors. Trends Pharmacol . Sci . 12: 34, 1991).
  • Several distinct receptor subunits have been cloned, and these subunits can be expressed, in Xenopus oocytes for example, to form functional receptors with their associated cation channels. It is hypothesized that such receptor-ionophore complexes are heteropentameric structures.
  • the possible role of nicotinic receptor-operated Ca 2+ channels in the pathology of neurological disorders and diseases such as ischemic stroke, epilepsy and neurodegenerative diseases has been largely unexplored.
  • arylalkylamine toxins also called polyamine toxins, arylamine toxins, acylpolyamine toxins or polyamine amide toxins
  • arylalkylamine toxins also called polyamine toxins, arylamine toxins, acylpolyamine toxins or polyamine amide toxins
  • Arylalkylamine toxins were initially reported to be selective antagonists of the AMPA/kainate subtypes of glutamate receptors in the mammalian CNS (Kawai et al . , Effect of a spider toxin on glutaminergic synapses in the mammalian brain. Biomed. Res. 3: 353, 1982; Saito et al .
  • Spider Toxin blocks glutamate synapse in hippocampal pyramidal neurons.
  • arylalkylamine spider toxins ( ⁇ - agatoxins) which antagonize NMDA receptor function in mammalian brain.
  • the authors discuss the mechanism of action of arylalkylamine toxins, and indicate that an NMDA receptor-operated ion channel is the probable site of action of the ⁇ -agatoxins, and most probably other spider venom arylalkylamines. They state:
  • NMDA receptor function is not well supported by two recent binding studies. Reynolds reported that argiotoxin 636 inhibits the binding of [ 3 H]MK-801 to rat brain membranes in a manner that is insensitive to glutamate, glycine, or spermidine. This author concluded that argiotoxin 636 exerts a novel inhibitory effect on the NMDA receptor complex by binding to one of the Mg 2+ sites located within the NMDA-gated ion channel. Binding data reported by Williams et al .
  • argiotoxin 636 does not act primarily at the polyamine modulatory site on the NMDA receptor, but rather acts directly to produce an activity-dependent block of the ion channel. It is already known that compounds such as phencyclidine and ketamine can block the ion channels associated with both arthropod muscle glutamate receptors and mammalian NMDA receptors. Thus, it seems possible that vertebrate and invertebrate glutamate receptors share additional binding sites for allosteric modulators of receptor function, perhaps related to divalent cation-binding sites. Clearly, considerable additional work will be needed to determine if the arylamines define such a novel regulatory site.
  • polyamines may antagonize responses to NMDA by interacting with membrane ion channels.
  • Seymour and Mena In vivo NMDA antagonist activity of the polyamine spider venom component, argiotoxin-636. Soc. Neurosci . Abst . 15: 1168, 1989) describe studies that are said to show that argiotoxin-636 does not significantly affect locomotor activity at doses that are effective against audiogenic seizures in DBA/2 mice, and that it significantly antagonizes NMDA-induced seizures with a minimal effective dose of 32 mg/kg given subcutaneously (s.c. ) .
  • Herold and Yaksh Anesthesia and muscle relaxation with intrathecal injections of AR636 and AG489, two acylpolyamine spider toxins, in rats.
  • Agel-489 and Agel-505 enhance the binding of [ 3 H]MK-801 to NMDA receptors on membranes prepared from rat brain by an action at the stimulatory polyamine receptor; polyamine receptor agonists occluded the stimulatory effects of Agel-489 and Agel-505 and polyamine receptor antagonists inhibited the stimulatory effect of Agel-505. Higher concentrations of Agel-489 and Agel-505, and argiotoxin-636 at all concentrations tested, had inhibitory effects on the binding of [ 3 H]MK-801.
  • Agel-505 inhibited responses to NMDA with an IC 50 of 13 nM; this effect of Agel- 505 occurred at concentrations approximately 10, 000-fold lower than those that affected [ 3 H]MK-801 binding. Responses to kainate were inhibited only 11% by 30 nM Agel-505. The antagonism of NMDA-induced currents by Agel-505 was strongly voltage-dependent, consistent with an open-channel blocking effect of the toxin. Williams states:
  • ⁇ -agatoxins can interact at the positive allosteric polyamine site on the NMDA receptor, stimulatory effects produced by this interaction may be masked in functional assays due to a separate action of the toxins as high- affinity, noncompetitive antagonists of the receptor.
  • Brackley et al. Steive antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins, J. Pharmacol . Exp. Therap. 266: 1573, 1993
  • the polyamine-containing toxins arylalkylamines
  • philanthotoxin-343 PhTX-343
  • argiotoxin-636 Arg-636
  • Arg-636 antagonizes subtypes of AMPA receptors in a voltage- and use-dependent manner consistent with open-channel blockade.
  • PhTX highly potent photoaffinity labeled philanthotoxin
  • arylalkylamines sometimes referred to as arylamine toxins, polyamine toxins, acylpolyamine toxins or polyamine amide toxins
  • arylalkylamines sometimes referred to as arylamine toxins, polyamine toxins, acylpolyamine toxins or polyamine amide toxins
  • arylalkylamines sometimes referred to as arylamine toxins, polyamine toxins, acylpolyamine toxins or polyamine amide toxins
  • these arylalkylamine compounds contain within their structure a polyamine moiety, they are unlike other known simple polyamines in possessing extremely potent and specific effects on certain types of receptor-operated Ca 2+ channels.
  • arylalkylamines Using native arylalkylamines as lead structures, a number of analogs were synthesized and tested. Initial findings on arylalkylamines isolated and purified from venom were confirmed utilizing synthetic arylalkylamines. These compounds are small molecules (mol. wt. ⁇ 800) with demonstrated efficacy in in vivo models of stroke and epilepsy.
  • the NMDA receptor-ionophore complex was used as a model of receptor-operated Ca 2+ channels. Selected arylalkylamines were shown to block NMDA receptor-mediated responses by a novel mechanism.
  • the unique behavioral pharmacological profile of these compounds suggests that they are unlikely to cause the PCP-like psychotomimetic activity and cognitive deficits that characterize other inhibitors of the NMDA receptor.
  • the arylalkylamines are unique amongst NMDA receptor antagonists in that they are able to antagonize certain subtypes of cloned and expressed AMPA receptors, namely, those permeable to Ca 2+ .
  • the arylalkylamines therefore, are the only known class of compounds able to antagonize glutamate receptor-mediated increases in cytosolic Ca 2+ regardless of the pharmacological definition of receptor subtype.
  • arylalkylamines inhibit another receptor-operated Ca 2+ channel, the nicotinic cholinergic receptor. Given that excessive and prolonged increases in cytosolic Ca 2+ have been implicated in the etiology of several neurological disorders and diseases, such arylalkylamines are valuable small molecule leads for the development of novel therapeutics for various neurological disorders and diseases.
  • Applicant has determined that the selected arylalkylamines bind with high affinity at a novel site on the NMDA receptor-ionophore complex which has heretofore been unidentified, and that said arylalkylamines do not bind with high affinity at any of the known sites (glutamate binding site, glycine binding site, MK-801 binding site, Mg 2+ binding site, Zn 2+ binding site, polyamine binding site, sig a binding site) on said NMDA receptor-ionophore complex.
  • This determination has allowed applicant to develop methods and protocols by which useful compounds can be identified which provide both therapeutically useful compounds and lead compounds for the development of other therapeutically useful compounds. These compounds can be identified by screening for compounds that bind at this novel arylalkylamine binding site, and by determining whether such a compound has the required biological, pharmacological and physiological properties.
  • the method includes the step of identifying a compound which binds to the receptor-operated Ca 2+ channel at that site bound by the arylalkylamine compounds referred to herein as Compound 1, Compound 2 or Compound 3, and having the structures shown below.
  • terapéuticaally useful compound is meant a compound that is potentially useful in the treatment of a disorder or disease state.
  • a compound uncovered by the screening method is characterized as having potential therapeutic utility in treatment because clinical tests have not yet been conducted to determine actual therapeutic utility.
  • neurodegenerative disease is meant a disorder or disease of the nervous system including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, spinal cord ischemia, ischemia- or hypoxia-induced nerve cell damage, hypoxia-induced nerve cell damage as in cardiac arrest or neonatal distress, epilepsy, anxiety, neuropsychiatric or cognitive deficits due to ischemia or hypoxia such as those that frequently occur as a consequence of cardiac surgery under cardiopulmonary bypass, and neurodegenerative disease.
  • neuroprotectant, anticonvulsant, anxiolytic, analgesic, muscle relaxant and/or adjunct in general anesthesia may be indicated, useful, recommended or prescribed.
  • neurodegenerative disease is meant diseases including, but not limited to, Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) .
  • ALS amyotrophic lateral sclerosis
  • neuroprotectant is meant a compound capable of preventing the neuronal damage or death associated with a neurological disorder or disease.
  • anticonvulsant is meant a compound capable of reducing convulsions produced by conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery.
  • anxiolytic is meant a compound capable of relieving the feelings of apprehension, uncertainty and fear that are characteristic of anxiety.
  • analgesic is meant a compound capable of relieving pain by altering perception of nociceptive stimuli without producing anesthesia or loss of consciousness.
  • muscle relaxant is meant a compound that reduces muscular tension.
  • adjunct in general anesthesia is meant a compound useful in conjunction with anesthetic agents in producing the loss of ability to perceive pain associated with the loss of consciousness.
  • potent or “active” is meant that the compound has activity at receptor-operated calcium channels, including NMDA receptors, Ca 2+ -permeable AMPA receptors, and nicotinic cholinergic receptors, with an IC 50 value less than 10 ⁇ M, more preferably less than 100 nM, and even more preferably less than 1 nM.
  • selective is meant that the compound is potent at receptor-operated calcium channels as defined above, but is less potent by greater than 10-fold, more preferably 50- fold, and even more preferably 100-fold, at other neurotransmitter receptors, neurotransmitter receptor- operated ion channels, or voltage-dependent ion channels.
  • biochemical and electrophysiological assays of receptor-operated calcium channel function is meant assays designed to detect by biochemical or electrophysiological means the functional activity of receptor-operated calcium channels.
  • assays include, but are not limited to, the fura-2 fluorimetric assay for cytosolic calcium in cultured rat cerebellar granule cells (see Example 1 and Example 2) , patch clamp electrophysiolocial assays (see Example 3 and Example 27), rat hippocampal slice synaptic transmission assays (see Example 5) , radioligand binding assays (see Example 4, Example 24, Example 25, and Example 26), and in vi tro neuroprotectant assays (see Example 6) .
  • ischemic and hemorrhagic stroke head trauma, spinal cord injury, spinal cord ischemia, ischemia- or hypoxia-induced nerve cell damage, hypoxia-induced nerve cell damage as in cardiac arrest or neonatal distress, neuropsychiatric or cognitive deficits due to ischemia or hypoxia such as those that frequently occur as a consequence of cardiac surgery under cardiopulmonary bypass, and neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) (see Examples 7 and 8, below) .
  • ALS amyotrophic lateral sclerosis
  • anticonvulsant activity is meant efficacy in reducing convulsions produced by conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery (see Examples 9 and 10, below) .
  • anxiolytic activity is meant that a compound reduces the feelings of apprehension, uncertainty and fear that are characteristic of anxiety.
  • analgesic activity is meant that a compound produces the absence of pain in response to a stimulus that would normally be painful. Such activity would be useful in clinical conditions of acute and chronic pain including, but not limited to the following: preemptive preoperative analgesia; peripheral neuropathies such as occur with diabetes mellitus and multiple sclerosis; phantom limb pain; causalgia; neuralgias such as occur with herpes zoster; central pain such as that seen with spinal cord lesions; hyperalgesia; and allodynia.
  • causalgia is meant a painful disorder associated with injury of peripheral nerves.
  • neuralgia pain in the distribution of a nerve or nerves .
  • central pain pain associated with a lesion of the central nervous system.
  • hypoalgesia an increased response to a stimulus that is normally painful.
  • pain due to a stimulus that does not normally provoke pain (see Examples 11 through 14, below) .
  • induction of long-term potentiation in rat hippocampal slices is meant the ability of tetanic electrical stimulation of afferent Schaffer collateral fibers to elicit long-term increases in the strength of synaptic transmission at the Schaffer collateral-CAl pyramidal cell pathway in rat hippocampal slices maintained in vitro (see Example 19) .
  • therapeutic dose is meant an amount of a compound that relieves to some extent one or more symptoms of the disease or condition of the patient. Additionally, by “therapeutic dose” is meant an amount that returns to normal, either partially or completely, physiological or biochemical parameters associated with or causative of the disease or condition. Generally, it is an amount between about 1 nmole and 1 ⁇ mole of the compound, dependent on its EC 50 (IC 50 in the case of an antagonist) and on the age, size, and disease associated with the patient.
  • impair cognition is meant the ability to impair the acquisition of memory or the performance of a learned task (see Example 20) .
  • impair congnition is meant the ability to interfere with normal rational thought processes and reasoning.
  • disrupt motor function is meant the ability to significantly alter locomotor activity (see Example 15) or elicit significant ataxia, loss of the righting reflex, sedation or muscle relaxation (see Example 16) .
  • locomotor activity is meant the ability to perform normal ambulatory movements.
  • loss of the righting reflex is meant the ability of an animal, typically a rodent, to right itself after being placed in a supine position.
  • neurovascular vacuolization is meant the production of vacuoles in neurons of the cingulate cortex or retrosplenial cortex (see Example 18) .
  • cardiovascular activity is meant the ability to elicit significant changes in parameters including, but not limited to, mean arterial blood pressure and heart rate (see Examples 21 and 22) .
  • hyperexcitability is meant an enhanced susceptibility to an excitatory stimulus. Hyperexcitability is often manifested as a significant increase in locomotor activity in rodents administered a drug (see Example 15) .
  • sedation is meant a calmative effect, or the allaying of activity and excitement. Sedation is often manifested as a significant decrease in locomotor activity in rodents administered a drug (see Example 15) .
  • PCP-like abuse potential is meant the potential of a drug to be wrongfully used, as in the recreational use of PCP (i.e., "angel dust") by man. It is believed that PCP- like abuse potential can be predicted by the ability of a drug to generalize to PCP in rodents trained to discriminate PCP from saline (see Example 17.) By “generalization to PCP” is meant that a compound is perceived as being PCP in rodents trained to discriminate PCP from saline (see Example 17) .
  • PCP-like psychotomimetic activity is meant the ability of a drug to elicit in man a behavioral syndrome resembling acute psychosis, including visual hallucinations, paranoia, agitation, and confusion. It is believed that PCP-like psychotomimetic activity can be predicted in rodents by the ability of a drug to produce PCP-like stereotypic behaviors including ataxia, head weaving, hyperexcitability, and generalization to PCP in rodents trained to discriminate PCP from saline (see Example 15, Example 16, and Example 17) .
  • Ataxia is meant a deficit in muscular coordination.
  • head weaving is meant the stereotypic behavior elicited in rodents by PCP in which the head is repeatedly moved slowly and broadly from side to side.
  • composition a therapeutically effective amount of a compound of the present invention in a pharmaceutically acceptable carrier, i.e., a formulation to which the compound can be added to dissolve or otherwise facilitate administration of the compound.
  • pharmaceutically acceptable carriers include water, saline, and physiologically buffered saline.
  • Such a pharmaceutical composition is provided in a suitable dose.
  • Such compositions are generally those which are approved for use in treatment of a specified disorder by the FDA or its equivalent in non-U.S. countries.
  • the invention features a method for treating a neurological disease or disorder, comprising the step of administering a pharmaceutical composition comprising a compound which binds to a receptor-operated calcium channel at the site bound by one of the arylalkylamines Compound 1, Compound 2 and Compound 3, said compound being a potent and selective noncompetitive antagonist at such a receptor-operated calcium channel, and having one or more of the following pharmacological and physiological properties: efficacy in in vitro biochemical and electrophysiological assays of receptor-operated calcium channel function, in vivo anticonvulsant activity, in vivo neuroprotectant activity, in vivo anxiolytic activity, and in vivo analgesic activity; said compound also possessing one or more of the following pharmacological effects: the compound does not interfere with the induction of long-term potentiation in rat hippocampal slices, and, at a therapeutic dose, does not impair cognition, does not disrupt motor performance, does not produce neuronal va
  • minimal is meant that any side effect of the drug is tolerated by an average individual, and thus that the drug can be used for therapy of the target disease.
  • side effects are well known in the art and are routinely regarded by the FDA as minimal when it approves a drug for a target disease.
  • Treatment involves the steps of first identifying a patient that suffers from a neurological disease or disorder by standard clinical methodology and then treating such a patient with a composition of the present invention.
  • the invention features compounds useful for treating a patient having a neurological disease or disorder wherein said compound is a polyamine-type compound or an analog thereof (i.e., a polyheteroatomic molecule) having the formula
  • Ar is an appropriately substituted aromatic ring, ring system or other hydrophobic entity
  • Ar can be an aromatic (e.g., carbocyclic aryl groups such as phenyl and bicyclic carbocyclic aryl ring systems such as naphthyl, 1,2,3, 4-tetrahydronaphthyl, indanyl, and indenyl), heteroaromatic (e.g., indolyl, dihydroindolyl, quinolinyl and isoquinolinyl, and their respective 1, 2, 3, 4-tetrahydro- and 2-oxo- derivatives) , alicyclic (cycloaliphatic) , or heteroalicyclic ring or ring system (mono-, bi-, or tricyclic) , having 5- to 7-membered ring(s) optionally substituted with 1 to 5 substituents independently selected from lower alkyl of 1 to 5 carbon atoms, lower haloalkyl of 1 to 5 carbon atoms substituted
  • Preferred aromatic headgroups include, but are not limited to, the following:
  • the compound is selected from the group of Compounds 4 through 18, where such compounds have the formulae:
  • Such simplified arylalkylamines possess one or more of the following additional biological properties: significant neuroprotectant activity, significant anticonvulsant activity, significant analgesic activity, no PCP-like stereotypic behavior in rodents (hyperexcitability and head weaving) at effective neuroprotectant, anticonvulsant and analgesic doses, no generalization to PCP in a PCP discrimination assay at effective neuroprotectant, anticonvulsant and analgesic doses, no neuronal vacuolization at effective neuroprotectant, anticonvulsant and analgesic doses, significantly less potent activity against voltage-sensitive calcium channels, and minimal hypotensive activity at effective neuroprotectant, anticonvulsant and analgesic doses.
  • Such compounds may, however, inhibit the induction of LTP in rat hippocampal slices and may produce motor impairment at neuroprotectant, anticonvulsant and analgesic doses.
  • One aspect of the invention features a method for treating a patient having a neurological disease or disorder, comprising administering a compound of Formula I:
  • R 1 and R 5 are independently selected from the group consisting of phenyl, benzyl, and phenoxy (each of which is optionally substituted with alkyl, hydroxyalkyl, -OH, -0- alkyl, -0-acyl, -F, -Cl, -Br, -I, -CF 3, or -0CF 3 ) , -H, alkyl, hydroxyalkyl, -OH, -0-alkyl, and 0-acyl;
  • R 2 and R 6 are independently selected from the group consisting of -H, alkyl, and hydroxyalkyl; or R 2 and R 6 together are imino; or R 1 and R 2 together are -(CH 2 ) n - or - (CH 2 ) n -N(R 3 )-(CH 2 ) n -; R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl and alkylphenyl; n is an integer from 0 to 6, but at least one n must be greater than 0;
  • R 4 is selected from the group consisting of thiofuran, pyridyl, phenyl, benzyl, phenoxy, and phenylthio (each of which is optionally substituted with alkyl, -F, -Cl, -Br, - I, -CF 3 , -OH, -OCF 3 , -0-alkyl, or -0-acyl) , -H, alkyl and cycloalkyl;
  • X is independently selected from the group consisting of phenyl, benzyl, and phenoxy (each of which is optionally substituted with -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -OCF 3 , - O-alkyl, or -O-acyl) -F, -Cl, -Br, -I, CF 3/ alkyl, -OH, - OCF 3 , -O-alkyl, and O-acyl; m is independently an integer from 0 to 5; Y is -NR 3 R 3 , except when R 1 and R 2 together are -(CH 2 ) n - N(R 3 ) -(CH 2 ) n -, then Y is -H; and pharmaceutically acceptable salts and complexes thereof, wherein the compound is active at an NMDA receptor.
  • patient is meant any animal that has a cell with an NMDA receptor.
  • the animal is a mammal.
  • the animal is a human.
  • alkyl is meant a branched or unbranched hydrocarbon chain containing between 1 and 6, preferably between 1 and 4, carbon atoms, such as, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, 2-methylpentyl, cyclopropylmethyl, allyl, and cyclobutylmethyl .
  • lower alkyl is meant a branched or unbranched hydrocarbon chain containing between 1 and 4 carbon atoms, of which examples are listed herein.
  • hydroxyalkyl is meant an alkyl group as defined above, substituted with a hydroxyl group.
  • alkylphenyl is meant an alkyl group as defined above, substituted with a phenyl group.
  • acyl is meant -C(0)R, where R is H or alkyl as defined above, such as, e.g., formyl, acetyl, propionyl, or butyryl; or,
  • R is -O-alkyl such as in alkyl carbonates or R is N- alkyl such as in alkyl carbamates.
  • cycloalkyl is meant a branched or unbranched cyclic hydrocarbon chain containing between 3 and 12 carbon atoms .
  • Y is selected from the group consisting of -NH 2 and -NH- methyl ;
  • R 4 is thiofuran, pyridyl, phenyl, benzyl, phenoxy, or phenylthio, each of which is optionally substituted with -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, or -O-acyl;
  • X is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-O-lower alkyl, ortho- methyl, ortho-fluoro, ortho-chloro, meta-O-lower alkyl, meta-methyl, ortho-OH, and meta-OH; and either R 1 , R 2 ' R 5 , and R 6 are -H; or R 2 is methyl, and R 1 , R 5 , and R 6 are -H; or R 1 is methyl, and R 2 , R 5 , and R 6 are -H.
  • R 1 and R 5 are independently selected from the group consisting of -H, lower alkyl, hydroxyalkyl, -OH, -0-alkyl, and -O-acyl;
  • R 2 and R 6 are independently selected from the group consisting of -H, lower alkyl, and hydroxyalkyl; or R 1 and R 2 together are -(CH 2 ) n - or -(CH 2 ) n -N(R 3 ) " , and Y is H; R 3 is independently selected from the group consisting of -H and lower alkyl;
  • R 4 is selected from the group consisting of thiofuran, pyridyl, phenyl, benzyl, phenoxy, and phenylthio (each of which is optionally substituted with lower alkyl, -F, -Cl, -Br, -I, -CF 3 , -OH, -OCF 3 , -O-alkyl, or -O-acyl), -H, lower alkyl, and cycloalkyl;
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, -CF 3 , lower alkyl, -OH, and -OCF 3 ;
  • m is independently an integer from 0 to 5;
  • Y is -NHR 3 , or hydrogen when R 1 and R 2 together are - (CH 2 ) n -N (R 3 ) -, and pharmaceutically acceptable salts and complexes thereof, with the provisos that
  • the invention features a method for treating a patient having a neurological disease or disorder comprising administering a compound of Formula II:
  • X is independently selected from the group consisting of -H, -Br, -Cl, -F, -I, -CF 3 , alkyl, -OH, -0CF 3 , -O-alkyl, and -O-acyl;
  • R 1 is independently selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl
  • R 2 is independently selected from the group consisting of -H, alkyl, and hydroxyalkyl, or both R 2 s together are imino
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl
  • m is independently an integer from 0 to 5.
  • the compounds include the compound of Formula I, wherein:
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, and - O-acyl;
  • R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • R 2 and R 6 are independently selected from the group consisting of -H, alkyl, and hydroxyalkyl, or R 2 and R 6 together are imino ;
  • R 5 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • Y is NR 3 R 3 ;
  • R 4 is phenyl, optionally substituted with alkyl, -F, - Cl, -Br, -I, -CF 3 , -OH, -OCF 3 , -O-alkyl, or -0-acyl.
  • the administered compound has the structure of Formula III:
  • X is independently selected from the group consisting of -H, -Br, -Cl, -F, -I, -CF 3 , alkyl, -OH, -0CF 3 , -0-alkyl, and -O-acyl.
  • R 1 is independently selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl
  • R 2 is independently selected from the group consisting of -H, alkyl, and hydroxyalkyl, or both R 2 s together are imino
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl;
  • R 4 is selected from the group consisting of thiofuran, pyridyl, phenyl, benzyl, phenoxy, and phenylthio, (each of which is optionally substituted with (X)m), alkyl, and cycloalkyl; and, m is independently an integer from 0 to 5.
  • the compounds include the compound of Formula I, wherein:
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, and ⁇ O-acyl;
  • R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • R 2 and R 6 are selected from the group consisting of -H, alkyl, and hydroxyalkyl, or R 2 and R 6 together are imino;
  • R 5 is independently selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • Y is NR 3 R 3 .
  • the administered compound has the structure of Formulas IV and V.
  • n is an integer from 1 to 6;
  • X is independently selected from the group consisting of -H, -Br, -Cl, -F, -I -CF 3 , alkyl, -OH, -OCF 3 , -0-alkyl, and -O-acyl;
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl; and m is independently an integer from 0 to 5.
  • the administered compounds include the compound of Formula I, wherein:
  • R 3 is independently selected from the group consisting of -H, and alkyl
  • R 4 is phenyl, optionally substituted with alkyl, -F, - Cl, -Br, -I, -CF 3 , -OH, -OCF 3 , -O-alkyl, or -O-acyl;
  • R 1 and R 2 together are -(CH 2 ) n - or - (CH 2 ) n -N (R 3 ) - .
  • the administered compound has the structure of Formulas VI and VII:
  • n is an integer from 1 to 6;
  • X is independently selected from the group consisting of -H, -Br, -Cl, -F, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, and -O-acyl;
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl;
  • R 4 is selected from the group consisting of thiofuran, pyridyl, phenyl, benzyl, phenoxy, and phenylthio (each of which is optionally substituted with (X)m), alkyl, and cycloalkyl; and m is independently an integer from 0 to 5.
  • the administered compounds include the compound of Formula I, wherein:
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, CF 3 , alkyl, -OH, -OCF 3 -O-alkyl, and - O-acyl-;
  • R 1 and R 2 together are -(CH 2 ) n - or - (CH 2 ) ⁇ -N(R 3 ) - .
  • X is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-O-lower alkyl, ortho- methyl, ortho-fluoro, ortho-chloro, meta-O-lower alkyl, meta-methyl, ortho-OH, and meta-OH;
  • NR 3 is selected from the group consisting of NH, N- methyl, and N-ethyl;
  • NR 3 R 3 is selected from the group consisting of NH 2 , NH- methyl, and NH-ethyl;
  • R 1 is selected from the group consisting of -H and methyl
  • R 2 is selected from the group consisting of -H and methyl; and R 4 is selected from the group consisting of phenyl, benzyl, and phenoxy, each of which is optionally substituted with alkyl, -F, -Cl, -Br, -F, -CF 3/ -OH, -OCF 3 , -O-alkyl, or -O-acyl.
  • X is meta-fluoro; each R 1 and R 2 is -H;
  • NR 3 is selected from the group consisting of NH and N- methyl;
  • NR 3 R 3 is selected from the group consisting of NH 2 and NH-methyl;
  • R 4 is selected from the group consisting of phenyl, benzyl, and phenoxy, each of which is optionally substituted with alkyl, -F, -Cl, -Br, -I, -CF 3 , -OH, -OCF 3 , -O-alkyl, or -O-acyl.
  • the invention features a method for treating a patient having a neurological disease or disorder comprising administering the compounds of Formula VIII:
  • X 1 and X 2 are independently selected from the group consisting of -F, -Cl, -CH 3 , -OH, and lower O-alkyl in the 1-, 3-, 1-, or 9-substituent positions; m is independently an integer from 0 to 2;
  • -NHR is selected from the group consisting of - NH 2 , -NHCH 3 , and -NHC 2 H 5 ;
  • R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -0-alkyl, and -O-acyl, and
  • R 2 is selected from the group consisting of -H, alkyl, hydroxyalkyl, and pharmaceutically acceptable salts and complexes thereof, wherein the compound is active at an NMDA receptor.
  • Z is —CH 2 CH 2 — ;
  • X 1 or X 2 is -F, or both X 1 and X 2 are -F; either R 1 or R 2 is methyl or both R 1 and R 2 are -H; and -NHR is selected from the group consisting of -NH 2 or -NHCH 3 .
  • the invention features a method for treating a patient having a neurological disease or disorder comprising administering the compounds of Formula IX:
  • W is selected from the group consisting of -CH 2 -, -0-, and -S-;
  • X 1 and X 2 are independently selected from the group consisting of -F, -Cl, -CH 3 , -OH, and lower O-alkyl; m is independently an integer from 0 to 2; -NHR is selected from the group consisting of -NH 2 , - NHCH 3 , and -NHC 2 H 5 ;
  • R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -0-alkyl, and -O-acyl;
  • R 2 is selected from the group consisting of -H, alkyl, hydroxyalkyl, and pharmaceutically acceptable salts and complexes thereof, wherein the compound is active at an NMDA receptor.
  • the administered compound is selected from the group consisting of Compound 128, 129, 130, 131, 132, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, and 215.
  • the methods of treatment include administration of a compound selected from Compounds 19 through 215, or pharmaceutically acceptable salts and complexes thereof.
  • the compound has an IC 50 ⁇ 10 ⁇ M at an NMDA receptor, more preferably ⁇ 2.5 ⁇ M, and most preferably - 0.5 ⁇ M at an NMDA receptor.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 19, 20, 21, 22, 23, 24, 25,
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 19, 20, 21, 22, 23, 24, 25, 27,
  • the compound is selected from the group consisting of Compound 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138, 139, 142, 144, 145, 148, 149, and 150, and pharmaceutically acceptable salts and complexes thereof.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 19, 20, 21, 22, 23, 24, 25, 27, 28, 30, 31, 32, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 91, 93, 94, 95, 96, 97, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug), 142, 144, 145, 147, 148, 149, and 150, and pharmaceutically acceptable salts and complexes thereof.
  • These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 20, 24, 25, 33, 50, 60, 66, 69, 103, 111, 118, 119, 120, 122, 136, 137, 138 (potential prodrug) , 142, 144, 145, 148, 149, and 150, and pharmaceutically acceptable salts and complexes thereof.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 20, 33, 50, 60, 119, and 144, and pharmaceutically acceptable salts and complexes thereof.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 33, 50, 60, 119, and 144, and pharmaceutically acceptable salts and complexes thereof.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 156, 157,
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ lO ⁇ M at an NMDA receptor.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 156, 157, 158, 159, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 181, 183, 184, 185, 186, 187, and pharmaceutically acceptable salts and complexes thereof.
  • a compound which is selected from the group consisting of Compound 156, 157, 158, 159, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 181, 183, 184, 185, 186, 187, and pharmaceutically acceptable salts and complexes thereof.
  • These compounds have an IC 50 ⁇ 2.5 ⁇ M at an NMDA receptor .
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ 2.5 ⁇ M at an NMDA receptor.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 156, 157, 158, 159, 161, 163, 164, 165, 167, 168, 169, 170, 171, 181, 186 and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 167, 168, 169, 170, 171, 181, 186 and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the invention provides a method for treating a patient having a neurological disease or disorder comprising administering a compound selected from the group consisting of Compounds 151 - 215, and pharmaceutically acceptable salts and complexes thereof.
  • the invention provides a method for treating a patient having a neurological disease or disorder comprising administering a compound selected from the group consisting of Compound 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 181, 185, 186, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215 and pharmaceutically acceptable salts and complexes thereof.
  • a compound selected from the group consisting of Compound 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 172,
  • the present invention provides simplified arylalkylamines comprising the compounds of Formulas I-IX and all preferred aspects of Formulas I-IX as set out above.
  • simplified arylalkylamines include, but are not limited to, Compounds 19 - 215, whose structures are provided below.
  • the compound has an IC 50 ⁇ 10 ⁇ M at an NMDA receptor. More preferably, the compound has an IC 50 ⁇ 5 ⁇ M, more preferably ⁇ 2.5 ⁇ M, and most preferably ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 21, 22, 23, 24, 25, 26, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 78, 79, 82, 83, 84, 88, 89, 90, 92, 93, 94, 95, 96, 98, 101, 102, 103, 105, 107, 108, 109, 111, 115, 116, 118, 119, 120, 121, 122, 124, 125, 126, 127, 129, 130, 131, 134, 135, 136, 137, 138 (potential prodrug), 139, 141, 142, 143, 144, 145, 148, 149, and 150.
  • These compounds are selected
  • the compound is selected from the group consisting of Compound 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138, 139, 142, 144, 145, 148, 149, and 150.
  • the compound is selected from the group consisting of Compound 21, 22, 23, 24, 25, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 108, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138 (potential prodrug), 139, 142, 144, 145, 148, 149, and 150.
  • the compound has an IC 50 ⁇ 2.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 21, 22, 23, 24, 25, 27, 28, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 93, 94, 95, 96, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug), 142, 144, 145, 148, 149, and 150.
  • These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 24, 25, 33, 50, 60, 66, 69, 103, 111, 118, 119, 120, 122, 136, 137, 138, 142, 144, 145, 148, 149, and 150.
  • the compound is selected from the group consisting of Compound 20, 33, 50, 60, 119, and 144. In more particularly preferred embodiments, the compound is selected from the group consisting of Compound 33, 50, 60, 119, and 144.
  • the compound is selected from the group consisting of Compound 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 181, 185, 186, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215 and pharmaceutically acceptable salts and complexes thereof.
  • the compound is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof.
  • the compound has an IC 50 ⁇ 10 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 157, 158, 159, 163, 164, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof.
  • the compound has an IC 50 ⁇ 2.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 157, 158, 159, 163, 164, 167, 168, 169, 170, 171, 181, 186, and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • composition of matter aspect of the present invention are known compounds whose chemical structures are covered by the generic formulae presented above .
  • compositions useful for treating a patient having a neurological disease or disorder are provided in a pharmaceutically acceptable carrier and appropriate dose.
  • compositions may be in the form of pharmaceutically acceptable salts and complexes, as is known to those skilled in the art.
  • the pharmaceutical compositions comprise the compounds of Formulas I-IX and all preferred aspects of Formulas I-IX as set out above.
  • Preferred pharmaceutical compositions comprise
  • the compound has an IC 50 ⁇ 10 ⁇ M at an NMDA receptor. More preferably the compound has an IC 50 ⁇ 5 ⁇ M, more preferably ⁇ 2.5 ⁇ M, and most preferably ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 100, 101, 102, 103, 105, 106, 107, 108, 109, 111, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126
  • the compound is selected from the group consisting of 21, 22, 23, 24, 25, 26, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 78, 79, 82, 83, 84, 88, 89, 90, 92, 93, 94, 95, 96, 98, 101, 102, 103, 105, 107, 108, 109, 111, 115, 116, 118, 119, 120, 121, 122, 124, 125, 126, 127, 129, 130, 131, 134, 135, 136, 137, 138 (potential prodrug) , 139, 141, 142, 143, 144, 145, 148, 149, and 150.
  • the compound is selected from the group consisting of 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 109, 111, 115, 118, 119, 120, 121, 122,
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 70, 75, 76, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 100, 101, 102, 103, 105, 106, 108, 109, 111, 115, 118, 119, 120, 121, 122, 125,
  • the compound is selected from the group consisting of 21, 22, 23, 24, 25, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 108, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138 (potential prodrug), 139, 142, 144, 145, 148, 149, and 150.
  • the pharmaceutical composition comprises a compound is selected from the group consisting of Compound 20, 21, 22, 23, 24, 25, 27, 28, 30, 31, 32, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 91, 93, 94, 95, 96, 97, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug), 142, 144, 145, 148, 149, and 150.
  • These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of 21, 22, 23, 24, 25, 27, 28, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 93, 94, 95, 96, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug), 142, 144, 145, 148, 149, and 150.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 24, 25, 33, 50, 60, 66, 69, 103, 111, 118, 119, 120, 122, 136, 137, 138, 142, 144, 145, 148, 149, and 150.
  • the compound is selected from the group consisting of Compound 24, 25, 33, 50, 60, 66, 69, 103, 111, 118, 119, 120, 122, 136, 137, 138, 142, 144, 145, 148, 149, and 150.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 33, 50, 60, 119, and 144.
  • the compound is selected from the group consisting of 33, 50, 60, 119, and 144.
  • the pharmaceutical composition comprises a compound selected from the group consisting of compound 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 181, 185, 186, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215 and pharmaceutically acceptable salts and complexes thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof, and a pharmaceutically acceptable carrier.
  • These compounds have an IC 50 ⁇ 10 ⁇ M at an NMDA receptor.
  • the pharmaceutical composition comprises a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166,
  • the pharmaceutical composition comprises a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 167,
  • phenyl groups such as those occurring in Compounds 20 or 60
  • lipophilic or semi-polar aromatic e.g., naphthyl, naphthoxy, benzyl, phenoxy, phenylthio
  • aliphatic alkyl, e.g., isopropyl
  • cycloaliphatic cycloalkyl, e.g., cyclohexyl
  • heterocyclic e.g., pyridyl, furanyl, thiofuranyl (thiophenyl)
  • other functional groups or systems as is well known in the art, will afford clinically useful compounds (structural homologs, analogs, and/or congeners) with similar biopharmaceutical properties and activity at the NMDA receptor (e.g., cf.
  • NMDA receptor-active compounds with similarly useful biopharmaceutical properties, such as Compound 88 (a modified "classical Hi-antihistamine-type" structure) , which can be further optimized for activity at the NMDA receptor by preparing, e.g., the corresponding compound (s) containing, e.g., (bis) (3-fluorophenyl) group (s), as taught by the present invention.
  • the propyl backbone of compounds such as 20 and 60 may also be modified successfully by the incorporation of ring systems (as in Compounds 102 and 111) and/or unsaturation (e.g., a double bond, as in Compounds 81, 106, 109, and 139) to afford further clinically useful NMDA receptor-active compounds of the present invention ( cf. compounds cited above) .
  • the invention features a method for making a therapeutic agent comprising the steps of screening for said agent by determining whether said agent is active on a receptor-operated calcium channel, and synthesizing said therapeutic agent in an amount sufficient to provide said agent in a therapeutically effective amount to a patient.
  • Said screening may be performed by methods known to those of ordinary skill in the art, and may, for example be performed by the methods set out herein. Those skilled in the art are also familiar with methods used to synthesize therapeutic agents in amounts sufficient to be provided in a therapeutically effective amount.
  • said receptor-operated calcium channel is an NMDA receptor.
  • said method further comprises the step of adding a pharmaceutically acceptable carrier to said agent.
  • said therapeutic agent comprises a compound of Formula I, as set out herein.
  • said therapeutic agent comprises a compound of Formula II, III, IV, V, VI, VII, VIII, or IX, as set out herein.
  • said therapeutic agent comprises a compound having a structure selected from the group consisting of Formulas I-IX, and all preferred aspects of said formulas as set out herein.
  • said therapeutic agent is selected from the group consisting of Compounds 19-215.
  • said therapeutic agent is provided to a patient having a neurological disease or disorder.
  • said screening comprises the step of identifying a compound which binds to said receptor-operated calcium channel at a site bound by one of the arylalkylamines Compound 1, Compound 2 , and Compound 3.
  • Radioligand binding techniques a radiolabeled arylalkylamine binding assay
  • a radiolabeled arylalkylamine binding assay a radiolabeled arylalkylamine binding assay
  • Data from such radioligand binding studies will also confirm that said compounds do not inhibit [ 3 H] arylalkylamine binding via an action at the known sites on receptor- operated Ca 2+ channels (such as the glutamate binding site, glycine binding site, MK-801 binding site, Zn 2+ binding site, Mg 2+ binding site, sigma binding site, or polyamine binding site on the NMDA receptor-ionophore complex) .
  • This screening test allows vast numbers of potentially useful compounds to be identified and screened for activity in the other assays.
  • Those skilled in the art will recognize that other rapid assays for detection of binding to the arylalkylamine site on receptor-operated Ca 2+ channels can be devised and used in this invention.
  • the gene(s) encoding the novel arylalkylamine binding site i.e., receptor
  • the gene(s) encoding the novel arylalkylamine binding site can be identified and cloned. This can be accomplished in one of several ways. For example, an arylalkylamine affinity column can be prepared, and solubilized membranes from cells or tissues containing the arylalkylamine receptor passed over the column. The receptor molecules bind to the column and are thus isolated. Partial amino acid sequence information is then obtained which allows for the isolation of the gene encoding the receptor.
  • cDNA expression libraries are prepared and subfractions of the library are tested for their ability to impart arylalkylamine receptors on cells which do not normally express such receptors (e.g., CHO cells, mouse L cells, HEK 293 cells, or Xenopus oocytes) .
  • arylalkylamine receptors e.g., CHO cells, mouse L cells, HEK 293 cells, or Xenopus oocytes
  • the library fraction containing the clone encoding the receptor is identified. Sequential subfractionation of active library fractions and assay eventually results in a single clone encoding the arylalkylamine receptor.
  • hybrid- arrest or hybrid-depletion cloning can be used.
  • Xenopus oocytes are injected with mRNA from an appropriate tissue or cell source (e.g., human brain tissue). Expression of the arylalkylamine receptor is detected as, for example, an autosomalpha-1 (IL-1
  • cDNA clones are tested for their ability to block expression of this receptor when cDNA or cRNA are hybridized to the mRNA of choice, prior to injection into Xenopus oocytes. The clone responsible for this effect is then isolated by the process described above. Once the receptor gene is isolated, standard techniques are used to identify the polypeptide or portion (s) thereof which is (are) sufficient for binding arylalkylamines (the arylalkylamine binding domain[s]). Further, using standard procedures, the entire receptor or arylalkylamine binding domain (s) can be expressed by recombinant technology.
  • Said receptor or binding domain (s) can be isolated and used as a biochemical reagent such that, rather than using a competitive assay exemplified below, a simple direct binding assay can be used. That is, a screen is set up for compounds which bind at the novel arylalkylamine receptor. In this way large numbers of compounds can be simultaneously screened, e.g., by passage through a column containing the novel arylalkylamine receptor or arylalkylamine binding domain, and analysis performed on compounds which bind to the column.
  • Additional testing utilizes the combination of molecular biological techniques (expression of cloned NMDA, AMPA or nicotinic cholinergic receptors) and patch clamp electrophysiological techniques.
  • molecular biological techniques expression of cloned NMDA, AMPA or nicotinic cholinergic receptors
  • patch clamp electrophysiological techniques Specifically, arylalkylamine analogs can be rapidly screened for potency at cloned and expressed subunits of the above-mentioned receptor- ionophore complexes.
  • Site-directed mutagenesis can be utilized in an effort to identify which amino acid residues may be important in determining arylalkylamine potency.
  • Desired properties of a drug include: high affinity and selectivity for receptor-operated Ca 2+ channels, such as those present in NMDA, AMPA and nicotinic cholinergic receptor-ionophore complexes (compared to responses mediated via other neurotransmitter receptors, neurotransmitter receptor-operated ion channels, or voltage-dependent ion channels) and a noncompetitive antagonism of said receptor- operated Ca 2+ channels.
  • the NMDA receptor-ionophore complex is utilized as an example of a receptor-operated Ca 2+ channel.
  • Activation of the NMDA receptor opens a cation-selective channel that allows the influx of extracellular Ca 2+ and Na + , resulting in increases in [Ca 2+ ]i and depolarization of the cell membrane.
  • Measurements of [Ca 2+ ]i ere used as primary assays for detecting the activity of arylalkylamine compounds on NMDA receptors. Purified arylalkylamines, synthetic aryl- alkylamines, and synthetic analogs of arylalkylamines were examined for activity in in vitro assays capable of measuring glutamate receptor activity.
  • arylalkylamines present in the venom of various spider species are structurally distinct but have the basic structure of the class represented by Compounds 1 through 3.
  • Other more simplified synthetic analogs generally consist of suitably substituted aromatic chromophoric groups attached to an alkyl (poly) amine moiety (see Compounds 19 through 215 below) .
  • a primary assay that provides a functional index of glutamate receptor activity and that allows high-throughput screening was developed.
  • Example 1 Potent noncompetitive inhibition of NMDA receptor function
  • Preferential inhibitory effects of arylalkylamines on NMDA receptor-mediated increases in [Ca 2+ ] ⁇ in cultured rat cerebellar granule cells were measured. Increases in [Ca 2+ ] x were elicited by the addition of NMDA/glycine (50 ⁇ M/1 ⁇ M) in the presence or absence of different concentrations of each test compound.
  • the IC 50 values were derived for each test compound using from 2 to 8 separate experiments per test compound, and the standard error level was less than 10% of the mean value for each compound.
  • arylalkylamines tested blocked increases in [Ca 2+ ]i in cerebellar granule cells elicited by NMDA/glycine.
  • the inhibitory effects of the arylalkylamines were not overcome by increasing the concentrations of NMDA or glycine. That is, no change was observed in the EC 50 for either NMDA or glycine.
  • the arylalkylamines are thus noncompetitive antagonists at the NMDA receptor-ionophore complex, and act neither at the glutamate nor the glycine binding sites.
  • Example 2 Activity against Kainate and AMPA receptor function Measurements of [Ca 2+ ]iin cerebellar granule cells can also be used to monitor activation of the native kainate or AMPA receptors present in this tissue. Although the increases in [Ca 2+ ] ⁇ evoked by these agonists are of a lesser magnitude than those evoked by NMDA/glycine, such responses are robust and can be used to precisely assess the specificity of action of arylalkylamines on pharmacologically defined glutamate receptor subtypes. Comparative measurements of [Ca 2+ ] revealed a clear distinction in the receptor selectivity of the arylalkylamines.
  • arylalkylamines within the two structural classes defined by Compound 1 and by Compound 2 were found to inhibit preferentially responses evoked by NMDA (showing about a 100-fold difference in potency) .
  • arylalkylamines such as Compound 1 and Compound 2 are potent and selective inhibitors of NMDA receptor-mediated responses in cerebellar granule cells.
  • Example 3 Patch clamp electrophysiolo ⁇ y studies
  • arylalkylamines could be distinguished from both Mg 2+ and MK-801, especially with respect to the voltage-dependence of their onset of action and reversibility of effect.
  • arylalkylamines such as Compound 1 and Compound 2 have a unique site of action. Although they act like MK-801 in some respects (noncompetitive open-channel blockade, discussed above), they fail to displace [ 3 H]MK-801 binding at concentrations that completely block NMDA receptor-mediated responses. Assays such as these also demonstrate that the arylalkylamines do not bind with high affinity to the known MK-801, Mg 2+ , or polyamine binding sites on the NMDA receptor-ionophore complex.
  • arylalkylamines possess a quite different behavioral profile from other noncompetitive antagonists of the NMDA receptor.
  • Glutamate-mediated transmission at synapses of Schaffer collateral fibers and CAl pyramidal cells was measured in slices of rat brain containing the hippocampus. This assay measures electrophysiologically the postsynaptic depolarization caused by the presynaptic release of glutamate, and can readily distinguish synaptic transmission mediated by NMDA or AMPA receptors.
  • Arylalkylamines like Compound 1, Compound 2 and Compound 3 were again found to exert preferential inhibitory effects on NMDA receptor- mediated responses, and depressed responses mediated by AMPA receptors only at much higher concentrations.
  • Compound 1 had an IC 50 for the NMDA receptor- mediated response of 20 ⁇ M, but an IC 50 for the AMPA receptor-mediated response of 647 ⁇ M.
  • arylalkylamines can selectively inhibit synaptic transmission mediated by NMDA receptors.
  • Other naturally occurring arylalkylamines present in the venom of Agelenopsis aperta likewise exert potent and selective inhibitory effects on NMDA receptor- mediated responses in the rat hippocampus.
  • Desired properties of a neuroprotectant drug include the following.
  • the drug can be administered by oral or injectable routes (i.e., it is not significantly broken down in the stomach, intestine or vascular system and thus reaches the tissues to be treated in a therapeutically effective amount) .
  • Such drugs are easily tested in rodents to determine their bioavailability.
  • the drug exhibits neuroprotectant activity (i.e., efficacy) when given after an ischemic insult (stroke, asphyxia) or traumatic injury (head trauma, spinal cord injury) .
  • the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuolization, cardio-vascular activity, PCP-like abuse potential, or PCP-like psychotomimetic activity.
  • NMDA and AMPA receptors play a major role in mediating the neuronal degeneration following a stroke and other ischemic/ hypoxic events (Choi, Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623, 1988) . Most of this evidence is based on the ability of competitive or noncompetitive antagonists of the NMDA or AMPA receptor to effectively block neuronal cell death in both in vitro and in vivo models of stroke. Compound 1, Compound 2 and Compound 4 were therefore examined for neuroprotectant effects in standard assays designed to detect such activity.
  • LDH lactate dehydrogenase
  • the effective concentrations of the arylalkylamines are higher than those of other noncompetitive NMDA receptor antagonists, but similar to those of competitive antagonists.
  • the effective concentrations of NMDA receptor antagonists vary depending on the particular experimental conditions and the type of cell studied (cortical, hippocampal, striatal) . This neuroprotectant effect likely results from the ability of these compounds to block the influx of extracellular Ca 2+ triggered by the NMDA receptor.
  • the first assay was the bilateral common carotid artery occlusion model of forebrain ischemia performed in the gerbil (Karpiak et al . , Animal models for the study of drugs in ischemic stroke. Ann . Rev. Pharmacol . Toxicol . 29: 403, 1989; Ginsberg and Busto, Rodent models of cerebral ischemia. Stroke 20: 1627, 1989) . Blood flow to the brain was interrupted for 7 minutes by clamping the carotid arteries. The test compounds were administered as a single dose given intraperitoneally (i.p.) 30 minutes after reinstating blood flow. During the course of these experiments, the core body temperature of the animals was maintained at 37 °C to prevent any hypothermic reaction.
  • NMDA receptor antagonists cause hypothermia and this effect can account for much of the protective effect of these compounds.
  • the brains were examined for neuronal cell death 4 days later by silver staining sections of the brain and quantifying death by morphometric analysis.
  • Compound 2 (20 mg/kg) significantly (p ⁇ 0.05) protected against neuronal cell death in all areas of the brain examined (region CAl of hippocampus, striatum and neocortex) .
  • the degree of protection is comparable to that achieved with similar doses of the noncompetitive NMDA antagonist, MK-801.
  • Compound 1 (10 mg/kg) produced a 23% reduction in the amount of neuronal death in region CAl of the gerbil hippocampus measured at 7 days post-ischemia, while Compound 4 (10 mg/kg) provided 90% protection.
  • Example 8 Middle cerebral artery occlusion
  • the middle cerebral artery model of stroke performed in the rat (Karpiak et al . , Animal models for the study of drugs in ischemic stroke. Ann. Rev. Pharmacol . Toxicol . 29: 403, 1989; Ginsberg and Busto, Rodent models of cerebral ischemia. Stroke 20: 1627, 1989) is different from the gerbil model because it results in a more restricted brain infarct, and thereby approximates a different kind of stroke (focal thrombotic stroke) .
  • one cerebral artery was permanently occluded by surgical ligation.
  • the test compounds were administered 30 minutes after the occlusion by a single intraperitoneal (i.p.) injection.
  • an ischemic infarct was produced by a photothrombotic method using the dye Rose Bengal.
  • Compound 4 10 mg/kg i.p. administered 30 min after the ischemic event, produced a 20% reduction in the volume of the infarct, similar to that seen with the noncompetitive NMDA receptor antagonist, MK-801.
  • MK-801. the middle cerebral artery was temporarily occluded by passing a small piece of suture thread through the carotid artery to the region of the middle cerebral artery. The suture thread was withdrawn after an ischemic period of 2 hr. Core body temperature was maintained at 37 °C.
  • Compound 1, Compound 2 and Compound 4 demonstrate neuroprotectant effects in several different in vivo models of stroke.
  • the gerbil assay is a model for transient global cerebral ischemia and hypoxia such as cardiac arrest or perinatal hypoxia.
  • the rat assays are models of permanent and temporary focal cerebral ischemia.
  • the finding that Compound 1 and Compound 4 are neuroprotective in the permanent focal stroke models is surprising because the accessibility of the drug to the site of infarction is limited to the penumbral region which generally is not large. Nonetheless, Compound 1 and Compound 4 significantly (p ⁇ 0.05) limited the extent of damage.
  • the compounds are effective when administered after the ischemic event.
  • Desired properties of an anticonvulsant drug include: the drug can be administered by oral or injectable routes, the drug exhibits effective anticonvulsant activity against several seizure types, including, but not limited to, simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery; and the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuolization, cardiovascular activity, PCP-like abuse potential, or PCP-like psychotomimetic activity.
  • the drug can be administered by oral or injectable routes, the drug exhibits effective anticonvulsant activity against several seizure types, including, but not limited to, simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery; and the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuo
  • Glutamate is the major excitatory transmitter in the brain, and thus may play a major role in seizure activity, and contribute to the pathogenesis of epilepsy.
  • Much of the evidence favoring a major role for glutamate receptors in epilepsy derives from pharmacological studies demonstrating that glutamate receptor agonists elicit seizures, and that NMDA and AMPA receptor antagonists are effective anticonvulsants when administered in vivo.
  • glutamate receptor agonists elicit seizures
  • NMDA and AMPA receptor antagonists are effective anticonvulsants when administered in vivo.
  • There are numerous in vivo models involving different kinds of seizures and behavioral effects that are relevant for clinically distinct forms of epilepsy It is thus prudent to test for effects in several models, because it may be an oversimplification to suppose that the same mechanism underlies all forms of seizure activity.
  • arylalkylamines In initial studies, the ability of arylalkylamines to block seizures induced by kainate, picrotoxin or bicuculline were examined. Each of these convulsants acts through a different mechanism and seizures elicited by kainate are qualitatively different from those elicited by picrotoxin or bicuculline. In these experiments, a fraction of Agelenopsis aperta venom containing several arylalkylamine toxins was administered intravenously (iv) 5 min before picrotoxin or bicuculline, and 5 min after kainate administration. The arylalkylamines diminished the seizures induced by all three of these agents.
  • arylalkylamines such as Compound 1 proved to be effective anticonvulsants in two such paradigms.
  • the first two models used DBA/2 mice which are prone to audiogenic seizures. Seizures were elicited by sound (bell tone at 109 dBs) or the intraperitoneal (ip) administration of NMDA (56 mg/kg) . The test substances were administered 15-30 min before the convulsant stimulus. The number of clonic seizures was recorded for 1 min following the audiogenic stimulus or for 15 min following the administration of NMDA.
  • Compound 1 Compound 2, and several other arylalkylamines such as Compound 3 and Compound 4 depressed seizures evoked by either stimulus.
  • Compound 2 had an ED 50 of 0.13 mg/kg s.c. for audiogenic stimulus and 0.083 mg/kg s.c. for NMDA stimulus.
  • the EC 50 for Compound 4 in the audiogenic seizure model (0.08 mg/kg) approached that for MK-801 (0.02 mg/kg) .
  • neither Compound 1 nor Compound 2 was effective at doses up to 50 mg/kg s.c. in reducing seizures in CF-1 mice elicited by i.p. NMDA.
  • Desired properties of an analgesic drug include: the drug can be administered by oral or injectable routes, the drug exhibits analgesic activity, the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuolization, cardiovascular activity, PCP-like abuse potential, or PCP-like psychotomimetic activity. Glutamate and NMDA receptor-mediated responses may play a role in certain kinds of pain perception (Dickenson, A cure for wind up: NMDA receptor antagonists as potential analgesics. Trends Pharmacol . Sci . 11: 302, 1990). The possible analgesic effects of Compound 1, Compound 2, Compound 3 and Compound 4 were therefore examined.
  • Classic analgesic drugs such as morphine
  • Nonsteroidal antiinflammatory agents are likewise effective in this model.
  • Compound 1 (2 mg/kg).
  • Compound 2 (2 mg/kg) and Compound 3 (1 mg/kg) depressed the writhing response by greater than 95% when administered s.c. or i.p. 30 minutes before PBQ.
  • Compound 1 and Compound 4 were found to inhibit acetic acid-induced writhing in mice following i.p. injection with IC 50 values of 10 mg/kg and 1 mg/kg, respectively.
  • Example 12 Hot plate test Compound 1 was tested for analgesic activity in an additional assay.
  • mice were administered test substances s.c. 30 min before being placed on a hot plate (50°C) .
  • the time taken to lick the feet or jump off the plate is an index of analgesic activity, and effective analgesics increase the latency to licking or jumping.
  • Morphine (5.6 mg/kg) increased the latency to jump by 765%.
  • Compound 1 was likewise effective in this assay and, at doses of 4 and 32 mg/kg, increased the latency to foot licking by 136% and the latency to jumping by 360%, respectively.
  • Example 13 Tail flick test In this standard assay, the thermal nociceptive stimulus was 52°C warm water with the latency to tail flick or withdrawal taken as the endpoint. Compound 1 (0.3 - 3 nmol) and Compound 4 (0.3 - 3 nmol) produced a dose- and time-dependent analgesic effect following i.th. administration. These arylalkylamines were similar to morphine (0.3 - 3 nmol) in terms of potency and efficacy. The NMDA receptor antagonist, MK-801, on the other hand, was ineffective in this assay (3-30 nmol) .
  • Example 14 Formalin test Male Sprague-Dawley rats were habituated to an observation chamber for at least 1 hr before receiving an injection of dilute formalin (5%) in a volume of 50 ⁇ l into the left rear paw. Behavioral responses were monitored immediately after s.c. injection of formalin into the dorsal surface of the paw by counting the number of flinches exhibited by the animal. Behaviors were monitored for at least 50 min after formalin injection and were recorded as early phase responses (0 - 10 min post-formalin) and late phase responses (20 - 50 min post-formalin) . Compounds were injected intrathecally (i.th.) 10 min prior to formalin
  • pre-treatment or 10 min after formalin (post-treatment) in a volume of 5 ⁇ l.
  • Intraplantal administration of formalin produced a typical biphasic response of flinching behavior, commonly described as the early and late phase responses.
  • This effect of pretreatment with the arylalkylamines was similar to that seen with pretreatment with morphine (1 - 10 nmol) or MK-801 (1 - 30 nmol) .
  • Compound 1 (0.3 - 10 nmol i.th.) administered after the formalin produced some inhibition of late-phase flinching, though significance was achieved only at the 10 nmol dose.
  • Compound 4 (0.3 - 10 nmol i.th.) administered after the formalin produced significant inhibition of late-phase flinching, with significance achieved at the 3 and 10 nmol doses.
  • This analgesic profile of activity of the arylalkylamines is similar to that seen with post-formalin administration of morphine (1 - 10 nmol) ; post-formalin administration of MK-801 (1 - 30 nmol), however, failed to affect late-phase flinching.
  • arylalkylamines such as Compound 1 and Compound 4 have significant analgesic activity in several rodent models of acute pain.
  • the formalin assay additionally demonstrates that arylalkylamines are effective in an animal model of chronic pain.
  • the arylalkylamines possess significant analgesic activity when administered after the formalin stimulus. This profile of activity clearly distinguishes the arylalkylamines from standard NMDA receptor antagonists such as MK-801.
  • NMDA receptors Given the important role NMDA receptors play in diverse brain functions, it is not surprising to find that antagonists of this receptor are typically associated with certain unwelcome side effects. In fact, it is this property that provides the major obstacle to developing therapies that target NMDA receptors.
  • the principal side effects which characterize both competitive and noncompetitive antagonists, are a PCP-like psychotomimetic activity, impairment of motor performance, sedation or hyperexcitability, impairment of cognitive abilities, neuronal vacuolization, or cardiovascular effects (Willetts et al . , The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol . Sci . 11: 423, 1990; Olney et al .
  • arylalkylamines The activity of arylalkylamines was examined in animal models that index motor impairment, sedation and psychotomimetic activity as well as both in vitro and in vivo models of learning and memory.
  • both competitive and noncompetitive antagonists of the NMDA receptor produce a PCP-like stereotypic behavior characterized by hyperactivity, head- weaving, and ataxia (Willetts et al . , The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol . Sci . 11: 423, 1990; Snell and Johnson, In: Excitatory Amino Acids in Health and Disease, John Wiley & Sons, p. 261, 1988) .
  • the first assay simply monitors locomotor activity during the first hour following peripheral (s.c. or i.p.) administration of test substance. Mice received a dose of Compound 1 15 min before being placed into activity chambers. Activity was quantified by counting the number of breaks in a phototube grid in a 60 min period. In this assay, MK-801 (0.25 mg/kg p.o.) causes a 2- to 3-fold increase in locomotor activity. However, Compound 1, even when tested at 32 mg/kg s.c, did not elicit hyperactivity and, in fact, tended to depress it.
  • Compound 2 was likewise without effect (p > 0.05) on motor performance in DBA/2 mice when administered at a dose of 20 mg/kg s.c. These doses are considerably higher than those required to prevent sound-induced seizures in DBA/2 mice (see Example 10 above) .
  • the second assay of acute motor impairment was the rotorod assay. In this assay, Frings and CF1 mice were injected with test compound and placed on a knurled rod which rotated at a speed of 6 rpm. The ability of the mice to maintain equilibrium for long periods of time was determined; those mice that were unable to maintain equilibrium on the rotorod for 1 min in each of 3 trials were considered impaired.
  • Compound 1 produced acute motor impairment in Frings mice with a TD 50 (that dose which produced motor toxicity in 50% of the test animals) of 16.8 mg/kg i.p. This dose is similar to that which prevents sound-induced seizures in Frings mice (see Example 10 above) .
  • TD 50 that dose which produced motor toxicity in 50% of the test animals
  • Compound 1 is administered i.e.v. In this case, no apparent motor toxicity was evident until the dose of Compound 1 exceeded 1.56 ⁇ g i.e.v. (>2 times the ED 50 of 0.63 ⁇ g) .
  • motor impairment in CF1 mice was noted with Compound 1 following i.e. v. administration of 4 ⁇ g.
  • Compound 4 Compound 9, Compound 12 and Compound 14 were administered to Frings mice by i.e.v. injection, and acute motor impairment was measured.
  • the TD 50 values for Compounds 4, 9, 12 and 14 were 8-16 ⁇ g, 14.8 ⁇ g, 30.2 ⁇ g and 30.8 ⁇ g, respectively. These TD 50 values were 2-3 times higher than the effective IC 50 values for anticonvulsant potency (see Example 10 above) ; a clear separation between effective and toxic doses was noted.
  • rats who have been trained to lever press for food reinforcement must select which of two levers in their cages is correct. The only stimulus they have for selecting the correct lever is their ability to detect whether they received a PCP or vehicle injection. After about two months of training, rats become very good at discriminating PCP from vehicle injections and can then be tested with other drugs to determine if they are discriminated as PCP. When tested in this procedure, other drugs which are known to produce a PCP-like intoxication substitute for PCP. These drugs include various PCP analogs such as ketamine and the noncompetitive NMDA receptor antagonist, MK-801.
  • Compound 1 (1 - 30 mg/kg i.p.) did not substitute for PCP, and thus was completely devoid of PCP-like discriminative stimulus effects. At 30 mg/kg i.p., only 1 of the 7 animals tested responded at all on either lever. It is thus clear that a behaviorally effective dosage range of Compound 1 was evaluated. As the ability of test compounds to produce PCP-like effects in rats is believed to be predictive of their ability to produce PCP-like psychotomimetic activity and abuse liability in humans, these results strongly suggest that the arylalkylamines such as Compound 1 will lack such deleterious side effects in man.
  • vacuolization a neurotoxic effect termed neuronal vacuolization.
  • vacuoles are found in particular central neurons, especially those in the cingulate cortex and retrosplenial cortex. No such vacuolization was present in rats treated with Compound 1 at the single high dose of 100 mg/kg i.p.
  • LTP long-term potentiation
  • Example 19 LTP assay The effects of selected arylalkylamines and literature standards were examined for effects on LTP in slices of rat hippocampus. As anticipated, all the conventional competitive (AP5 and AP7) and noncompetitive (MK-801 and ifenprodil) NMDA receptor antagonists inhibited the induction of LTP in the hippocampus. Slices of rat hippocampus were superfused for 30-60 min with a test compound before delivering a tetanizing stimulus consisting of 3 trains, separated by 500 msec, of 100 Hz for 1 sec each. The response amplitude was monitored for an additional 15 minutes post-tetanus.
  • the tetanizing stimulus caused a mean 95% increase in the amplitude of the synaptic response.
  • the induction of LTP was significantly blocked (p ⁇ 0.05) by competitive (AP5, AP7) or noncompetitive (MK-801, ifenprodil) NMDA receptor antagonists.
  • AP5, AP7 competitive
  • MK-801, ifenprodil noncompetitive NMDA receptor antagonists.
  • none of the arylalkylamines tested blocked the induction of LTP (p > 0.05), even when used at high concentrations (100-300 ⁇ M) that caused some inhibition of the control response.
  • Arylalkylamines are the first, and at present the only, class of compounds shown to be selective and potent antagonists of the NMDA receptor that do not block the induction of LTP. This likely reflects the novel mechanism and site of action of arylalkylamines and suggests that drugs which target the novel site on the NMDA receptor will similarly lack effects on LTP. As LTP is the primary cellular model for learning and memory in the mammalian CNS, it additionally suggests that such drugs will lack deleterious effects on cognitive performance.
  • arylalkylamines are quite potent inhibitors of voltage-sensitive Ca 2+ channels, specifically those sensitive to inhibition by dihydropyridines (L-type channels) .
  • Such effects on vascular smooth muscle would be expected to dilate blood vessels and cause a drop in blood pressure, thus producing hypotension.
  • Arylalkylamines are not, however, indiscriminate blockers of voltage-sensitive Ca 2+ channels. They do not, for example, affect voltage-sensitive Ca 2+ channels in cerebellar Purkinje cells (P-type channels) or those channels thought to be involved in neurotransmitter release (N-channels) .
  • the arylalkylamines that do block voltage- sensitive Ca 2+ channels appear to target specifically L-type Ca 2+ channels.
  • there is a high degree of structural specificity in this effect For example, one arylalkylamine is 57 times more potent than another arylalkylamine in blocking Ca 2+ influx through L-type channels, where the only structural difference between the compounds is the presence or absence of a hydroxyl group.
  • Example 22 In vivo cardiovascular studies
  • the arylalkylamines Compound 1 and Compound 2 produce moderate drops (20-40 mm Hg) in mean arterial blood pressure (MABP) in anesthetized rats at doses which are effective in the in vivo stroke models (10-30 mg/kg s.c).
  • MABP mean arterial blood pressure
  • Compound 4 elicited a marked drop (40 mm Hg) in mean arterial pressure which persisted for approximately 90-120 min when administered at the dose of 10 mg/kg i.p.; it was in this same group of rats that Compound 4 afforded significant neuroprotection in the suture model of middle cerebral artery occlusion (see Example 8 above) . Similar results were obtained in the rat study in which
  • Compound 4 demonstrated neuroprotectant activity in the Rose Bengal photothrombotic model of focal ischemic stroke (see Example 8 above) . Further studies using the pithed rat preparation strongly suggest that the hypotensive activity of Compound 4 is a peripherally mediated effect. The hypotension and bradycardia produced by Compound 4 was maintained in rats pretreated with atropine, suggesting that these effects are not mediated by a cholinergic mechanism. Similarly, Compound 4 elicited hypotension and bradycardia in chemically sympathectomized rats (pretreated with a ganglionic blocker) , suggesting that these effects are not mediated via the sympathetic nervous system.
  • Example 23 Biological activity of Compound 19 and analogs Compounds 19 - 215 had high potencies against NMDA- induced increases in [Ca 2+ ]i in rat cerebellar granule cells grown in culture (Table 1) . The inhibitory effect of Compound 19 on responses to NMDA was noncompetitive. Compounds 19 - 215 inhibited [ 3 H]MK-801 binding in membranes prepared from rat hippocampal and cortical tissue (Table 1) . Compound 19 possessed the following additional biological activities: significant (p ⁇ 0.05 compared to control) anticonvulsant activity against maximal electroshock-induced seizures in mice following i.p.
  • Metrazol test in mice at the dose of 10 mg/kg i.p. significant neuroprotectant activity in a rat model of temporary focal ischemia (a 51% reduction in the infarct volume following the administration of two doses of 1 mg/kg i.p., the first given immediately after middle cerebral artery occlusion and the second given 6 hr later; a 43% reduction in the infarct volume following the administration of two doses of 1 mg/kg i.p., the first given 2 hr after middle cerebral artery occlusion (i.e., at the time of reperfusion) and the second given 6 hr later) ; significant neuroprotectant activity (a 24% reduction in the infarct volume) in a rat model of permanent focal ischemia following the administration of 1 mg/kg i.p.
  • Compound 22 possessed the following additional biological activities: significant anticonvulsant activity against sound-induced seizures in a genetically susceptible mouse model of reflex epilepsy (Frings mice) following i.p.
  • Compound 50 (an enantiomer of Compound 22) possessed the following additional biological activities: significant anticonvulsant activity against sound-induced seizures in a genetically susceptible mouse model of reflex epilepsy (Frings mice) following i.p.
  • TD 50 (motor impairment) 100.7 mg/kg.
  • TD 50 (motor impairment) 108.4 mg/kg; a significant increase in seizure threshold as indexed by the i.v.
  • Example 24 Radioligand binding in rat cortex or cerebellum
  • the following assay can be utilized as a high throughput assay to screen product libraries (e.g., natural product libraries and compound files at major pharmaceutical companies) to identify new classes of compounds with activity at this unique arylalkylamine site. These new classes of compounds are then utilized as chemical lead structures for a drug development program targeting the arylalkylamine binding site on receptor-operated Ca 2+ channels.
  • product libraries e.g., natural product libraries and compound files at major pharmaceutical companies
  • These new classes of compounds are then utilized as chemical lead structures for a drug development program targeting the arylalkylamine binding site on receptor-operated Ca 2+ channels.
  • the compounds identified by this assay offer a novel therapeutic approach to treatment of neurological disorders or diseases. Examples of such compounds include those provided in the generic chemical formulae above. Routine experiments can be performed to identify those compounds having the desired activities.
  • Rat brain membranes are prepared according to the method of Williams et al . (Effects of polyamines on the binding of [ 3 H]MK-801 to the NMDA receptor: Pharmacological evidence for the existence of a polyamine recognition site. Molec. Pharmacol . 36: 575, 1989) with the following alterations: Male Sprague-Dawley rats (Harlan Laboratories) weighing 100-200 g are sacrificed by decapitation. The cortex or cerebellum from 20 rats are cleaned and dissected. The resulting brain tissue is homogenized at 4°C with a polytron homogenizer at the lowest setting in 300 ml 0.32 M sucrose containing 5 mM K-EDTA (pH 7.0).
  • the homogenate is centrifuged for 10 min at 1,000 x g and the supernatant removed and centrifuged at 30,000 x g for 30 minutes.
  • the resulting pellet is resuspended in 250 ml 5 mM K-EDTA (pH 7.0) stirred on ice for 15 min, and then centrifuged at 30,000 x g for 30 minutes.
  • the pellet is resuspended in 300 ml 5 mM K-EDTA (pH 7.0) and incubated at 32°C for 30 min. The suspension is then centrifuged at 100,000 x g for 30 min.
  • Membranes are washed by resuspension in 500 ml 5 mM K- EDTA (pH 7.0), incubated at 32°C for 30 min, and centrifuged at 100,000 x g for 30 minutes. The wash procedure, including the 30 min incubation, is repeated. The final pellet is resuspended in 60 ml 5 mM K-EDTA (pH 7.0) and stored in aliquots at -80°C. The extensive washing procedure utilized in this assay was designed in an effort to minimize the concentrations of glutamate and glycine (co- agonists at the NMDA receptor-ionophore complex) present in the membrane preparation.
  • Nonspecific binding is determined in the presence of 100 ⁇ M nonradioactive arylalkylamine.
  • Duplicate samples are incubated at 0°C for 1 hour.
  • Assays are terminated by the addition of 3 ml of ice-cold buffer A, followed by filtration over glass-fiber filters (Schleicher & Schuell No. 30) that are presoaked in 0.33% polyethyleneimine (PEI) .
  • the filters are washed with another 3 x 3 ml of buffer A, and radioactivity is determined by scintillation counting at an efficiency of 35- 40% for 3 H.
  • PKI polyethyleneimine
  • [ 3 H] arylalkylamine to the filters is determined by passing 500 ⁇ l of buffer A containing various concentrations of [ 3 H] arylalkylamine through the presoaked glass-fiber filters.
  • the filters are washed with another 4 x 3 ml of buffer A, and radioactivity bound to the filters is determined by scintillation counting at an efficiency of 35-40% for 3 H.
  • radioactivity bound to the filters is determined by scintillation counting at an efficiency of 35-40% for 3 H.
  • PEI Presoaking with 0.33% PEI reduces the nonspecific binding to 0.5 - 1.0% of the total ligand added.
  • a saturation curve is constructed by resuspending SPMs in buffer A.
  • the assay buffer 500 ⁇ l
  • Concentrations of [ 3 H] arylalkylamine are used, ranging from 1.0 nM to 400 ⁇ M in half-log units.
  • a saturation curve is constructed from the data, and an apparent K D value and B M!1 value determined by Scatchard analysis (Scatchard, The attractions of proteins for small molecules and ions. Ann. N. Y. Acad. Sci . 51: 660, 1949).
  • the cooperativity of binding of the [ 3 H] arylalkylamine is determined by the construction of a Hill plot (Hill, A new mathematical treatment of changes of ionic concentrations in muscle and nerve under the action of electric currents, with a theory to their mode of excitation. J. Physiol . 40: 190, 1910) .
  • the dependence of binding on protein (receptor) concentration is determined by resuspending SPMs in buffer A.
  • the assay buffer 500 ⁇ l
  • the specific binding of [ 3 H] arylalkylamine should be linearly related to the amount of protein (receptor) present.
  • the time course of ligand-receptor binding is determined by resuspending SPMs in buffer A.
  • the assay buffer 500 ⁇ l contains a concentration of [ 3 H] arylalkylamine equal to its K D value and 100 ⁇ g of protein. Duplicate samples are incubated at 0°C for varying lengths of time; the time at which equilibrium is reached is determined, and this time point is routinely used in all subsequent assays.
  • the pharmacology of the binding site can be analyzed by competition experiments. In such experiments, the concentration of [ 3 H] arylalkylamine and the amount of protein are kept constant, while the concentration of test (competing) drug is varied.
  • This assay allows for the determination of an IC 50 and an apparent K D for the competing drug (Cheng and Prusoff, Relationship between the inhibition constant (K and the concentration of inhibitor which causes 50 percent inhibition (IC 50 ) of an enzymatic reaction. J. Biochem . Pharmacol . 22: 3099, 1973).
  • the cooperativity of binding of the competing drug is determined by Hill plot analysis.
  • Specific binding of the [ 3 H] arylalkylamine represents binding to a novel site on receptor-operated Ca 2+ channels such as those present within NMDA-, AMPA- and nicotinic cholinergic receptor-ionophore complexes. As such, other arylalkylamines should compete with the binding of
  • [ 3 H] arylalkylamine in a competitive fashion should correlate with their inhibitory potencies in a functional assay of receptor- operated Ca 2+ channel antagonism (e.g., inhibition of NMDA receptor-induced increases in [Ca 2+ ]i in cultures of rat cerebellar granule cells) .
  • receptor- operated Ca 2+ channel antagonism e.g., inhibition of NMDA receptor-induced increases in [Ca 2+ ]i in cultures of rat cerebellar granule cells
  • compounds which have activity at the other known sites on receptor-operated Ca 2+ channels e.g., MK-801, Mg 2+ , polyamines
  • Example 25 Radioligand binding in cerebellar granule cells Primary cultures of cerebellar granule neurons are obtained from 8-day-old rats and plated onto squares of Aclar plastic coated with poly-L-lysine. The plastic squares are placed in 24-well culture plates, and approximately 7.5 X 10 5 granule cells are added to each well.
  • Cultures are maintained in Eagles' medium (HyClone Laboratories) containing 25 mM KC1, 10% fetal calf serum (HyClone Laboratories) , 2 mM glutamine, 100 ⁇ g/ml gentamicin, 50 U/ml penicillin, and 50 ⁇ g/ml streptomycin at 37°C in a humid atmosphere of 5% C0 2 in air for 24 hr before the addition of cytosine arabinoside (10 ⁇ M, final) . No changes of culture medium are made until the cells are used for receptor binding studies 6-8 days after plating.
  • the reaction mixture consists of 200 ⁇ l of buffer A (20 mM K- HEPES, 1 mM K-EDTA, pH 7.0) in each well of the 24-well plate.
  • the [ 3 H] arylalkylamine is added to this reaction mixture.
  • Nonspecific binding is determined in the presence of 100 ⁇ M nonradioactive arylalkylamine.
  • Triplicate samples are incubated at 0°C for 1 hour. Assays are terminated by manually scraping the cells off the Aclar squares and placing them into polypropylene test tubes.
  • the membranes prepared from whole cells in this manner are suspended in 10 ml of ice-cold buffer A, and filtered over glass-fiber filters (Schleicher & Schuell No. 30) that are presoaked in 0.33% PEI.
  • the filters are washed with another 3 x 3 ml of buffer A, and radioactivity on the filters is determined by scintillation counting at an efficiency of 35-40% for 3 H.
  • the assay may be terminated by centrifugation rather than filtration in order to minimize nonspecific binding.
  • the binding assay allows for the determination of an IC 50 value and an apparent K D for the competing drug as described by Scatchard analysis (The attractions of proteins for small molecules and ions. Ann . N. Y. Acad. Sci . 51: 660, 1949). Cooperativity of binding of the competing drug is determined by Hill plot analysis (A new mathematical treatment of changes of ionic concentrations in muscle and nerve under the action of electric currents, with a theory to their mode of excitation. J. Physiol . 40: 190, 1910).
  • the specific binding of the [ 3 H] arylalkylamine represents binding to a novel site on receptor-operated calcium channels.
  • a rapid screening assay for useful compounds of this invention a cDNA or gene clone encoding the arylalkylamine binding site (receptor) from a suitable organism such as a human is obtained using standard procedures. Distinct fragments of the clone are expressed in an appropriate expression vector to produce the smallest polypeptide (s) obtainable from the receptor which retain the ability to bind Compound 1, Compound 2 or Compound 3. In this way, the polypeptide (s) which includes the novel arylalkylamine receptor for these compounds can be identified.
  • Such experiments can be facilitated by utilizing a stably transfected mammalian cell line (e.g., HEK 293 cells) expressing the arylalkylamine receptor.
  • the arylalkylamine receptor can be chemically reacted with chemically modified Compound 1, Compound 2 or Compound 3 in such a way that amino acid residues of the arylalkylamine receptor which contact (or are adjacent to) the selected compound are modified and thereby identifiable.
  • the fragment (s) of the arylalkylamine receptor containing those amino acids which are determined to interact with Compound 1, Compound 2 or Compound 3 and are sufficient for binding to said molecules can then be recombinantly expressed, as described above, using a standard expression vector (s).
  • the recombinant polypeptide (s) having the desired binding properties can be bound to a solid phase support using standard chemical procedures.
  • This solid phase, or affinity matrix may then be contacted with Compound 1, Compound 2 or Compound 3 to demonstrate that those compounds can bind to the column, and to identify conditions by which the compounds may be removed from the solid phase.
  • This procedure may then be repeated using a large library of compounds to determine those compounds which are able to bind to the affinity matrix, and then can be released in a manner similar to Compound 1, Compound 2 or Compound 3.
  • alternative binding and release conditions may be utilized in order to obtain compounds capable of binding under conditions distinct from those used for arylalkylamine binding (e.g., conditions which better mimic physiological conditions encountered especially in pathological states) .
  • Those compounds which do bind can thus be selected from a very large collection of compounds present in a liquid medium or extract.
  • native arylalkylamine receptor can be bound to a column or other solid phase support. Those compounds which are not competed off by reagents which bind other sites on the receptor can then be identified. Such compounds define novel binding sites on the receptor. Compounds which are competed off by other known compounds thus bind to known sites, or bind to novel sites which overlap known binding sites. Regardless, such compounds may be structurally distinct from known compounds and thus may define novel chemical classes of agonists or antagonist which may be useful as therapeutics. In summary, a competition assay can be used to identify useful compounds of this invention.
  • Example 27 Patch-clamp electrophysiology assay The following assay is performed for selected compounds identified in the above-mentioned radioligand binding assays as interacting in a highly potent and competitive fashion at the novel arylalkylamine binding site on receptor-operated Ca 2+ channels, such as those present in NMDA-, AMPA- or nicotinic cholinergic receptor-ionophore complexes. This patch-clamp assay provides additional relevant data about the site and mechanism of action of said previously selected compounds.
  • the following pharmacological and physiological properties of the compounds interacting at the arylalkylamine binding site are determined, utilizing the NMDA receptor-ionophore complex as an example of receptor- operated Ca 2+ channels: potency and efficacy at blocking NMDA receptor-mediated ionic currents, the noncompetitive nature of block with respect to glutamate and glycine, use- dependence of action, voltage-dependence of action, both with respect to onset and reversal of blocking, the kinetics of blocking and unblocking (reversal) , and open-channel mechanism of blocking.
  • patch-clamp experiments can be performed on Xenopus oocytes or on a stably transfected mammalian cell line (e.g., HEK 293 cells) expressing specific subunits of receptor-operated Ca 2+ channels.
  • a stably transfected mammalian cell line e.g., HEK 293 cells
  • potency and efficacy at various glutamate receptor subtypes e.g., NMDARl, NMDAR2A through NMDAR2D, GluRl through GluR4
  • Further information regarding the site of action of the arylalkylamines on these glutamate receptor subtypes can be obtained by using site- directed mutagenesis.
  • Arylalkylamines such as Compound 1, Compound 2 and
  • Compound 3 are synthesized by standard procedures (Jasys et al . , The total synthesis of argiotoxins 636, 659 and 673.
  • Synthesis of Compound 20 was accomplished as follows. A solution of sodium hydride (1.21 g, 50 mmol) in dimethoxyethane was treated with diethyl cyanomethyl- phosphonate (8.86 g, 50 mmol) and the reaction stirred 4 hr at room temperature. To this was added 3,3'- difluorobenzophenone (10 g, 46 mmol) in DME. The reaction was stirred 24 hr at room temperature, quenched with H 2 0, and partitioned between diethyl ether and water. The ether fraction was dried over Na 2 S0 4 and concentrated. GC/MS of this material showed 90% of the product A and 10% starting benzophenone .
  • each of the enantiomers 4 and 5 was reduced separately using dimethyl sulfideborane complex in the following manner.
  • a solution of compound (4 or 5 ) in THF was heated to reflux and treated with excess (2 Eq.) 1M (in THF) dimethyl sulfideborane complex and the reaction refluxed 30 min. After this time the reaction was cooled to 0°C and treated with 6 N HCI. The reaction was set to reflux for 30 min. After this time the reaction was transferred to a separatory funnel, basified to pH > 12 with ION NaOH, and the product (6 or 7) extracted into ether. The ether layer was washed with brine, dried over anhydrous MgS0 4 and concentrated to an oil.
  • the absolute configuration of Compound 33 -HI was determined to be R by single-crystal (monoclinic colorless needle, 0.50 x 0.05 x 0.03 mm) X-ray diffraction analysis using a Siemens R3m/V diffractometer (3887 observed reflections) .
  • a suspension of magnesium turnings (0.95 g, 39.2 mmol) in 150 ml anhydrous diethyl ether was treated with 1-bromo- 3-fluorobenzene (6.83 g, 39.2 mmol) dropwise via syringe. After 1.5 hr the solution was transfered via cannula to a flask containing o-anisaldehyde (5.0 g, 36.7 mmol) in 100 ml anhydrous diethyl ether at 0°C and stirred 2hr. The reaction mixture was quenched with water and partitioned between water and ether.
  • Compounds 101 and 103 were synthesized from Compounds 25 and 24, respectively, by cleavage of their O-methyl ethers with borane tribromide in the normal manner.
  • the ketone B (1.3 g, 4.9 mmol) was added to a solution of methoxylamine hydrochloride (0.45 g, 5.38 mmol) and pyridine (0.44 ml, 5.38 mmol) in 30 ml of ethanol, and stirred overnight. The ethanol was then evaporated, and the residue taken up in ether and 10% HCI. The ether layer was separated, washed once with 10% HCI, dried over sodium sulfate and evaporated to give 1.4 g of the O-methyl oxime.
  • Compound 50 was also prepared using the chiral synthesis described below.
  • the reaction was cooled to -78°C in a dry ice/isopropanol bath and then a solution of benzyl crotonate (15.0 g, 85.2 mmol) in THF (100 ml) was added dropwise over a period of 45 min.
  • the reaction was stirred at -78°C for 15 min, and then saturated NH 4 C1 (50 ml) was added.
  • the reaction mixture was then quickly transferred to a separatory funnel containing saturated NaCl (500 ml) and ether (200 ml) . The layers were separated and the aqueous layer extracted with ether (200 ml) .
  • Product B (20.02 g, 42.45 mmol, theoretical) was dissolved in acetic acid (120 ml) and sulfuric acid (30 ml) . The reaction was stirred at 90°C for 1 hr. The acetic acid was rotary evaporated giving a brown sludge. This material was placed in an ice bath and cold water (400 ml) was added. The product immediately precipitated. To the reaction was slowly added 10 N NaOH (150 ml) to neutral pH. Diethyl ether (200 ml) was added to this mixture. The mixture was shaken until there was no undissolved material.
  • the alcohol A was synthesized from 3-fluorobromo- benzene and 3-fluoro-2-methylbenzaldehyde as described for product A in the synthesis of Compound 24.
  • the alcohol A (8.4 g, 36.2 mmol) was stirred with manganese dioxide (12.6 g, 144.8 mmol) in 100 ml of dichloromethane for 4 days.
  • the reaction mixture was then diluted with ether and filtered through a 0.2 micron teflon membrane filter. The filtrate was concentrated to give 7.6 g of the ketone B.
  • the substituted acrylonitrile C was synthesized as described for product A in the Compound 20 synthesis.
  • ketone A was converted to Compound 57 as described for Compound 56.
  • nitrile B (1 g, 3.48 mmol) was dissolved in 30 ml of ethanol and 3 ml of 10 N sodium hydroxide. To this solution was added 1 g of a 50% aqueous slurry of Raney nickel, and the mixture was hydrogenated at 60 psi for 20 hours. The reaction was filtered and concentrated to a white solid. This residue was taken up in ether/water and the ether layer separated. The ether solution was dried over sodium sulfate and concentrated to give 0.96 g of the hydroxyamine C.
  • the hydroxyamine C (0.96 g, 3.3 mmol) was taken up in concentrated HCI and heated to 70°C which caused brief solution, and then precipitation of the alkene D.
  • the alkene was collected by filtration and dissolved in 30 ml of ethanol and 1 ml of cone. HCI. Palladium dihydroxide on carbon (0.4 g) was added to the solution, and the mixture hydrogenated at 60 psi for 24 hours. The product was isolated by filtering off the catalyst and evaporating the solvent.
  • Compound 60 was accomplished as follows. Compounds 66, 69, 108, 123, 142, and 145 can be synthesized in a similar manner starting from Compounds 33, 50, 32, 60, 25 and 119, respectively. Compound 20 (as the free base) (1.0 g, 4.0 mmol) was refluxed in ethyl formate (150 ml) for 2 hr. The solvent was then removed under reduced pressure to provide 1.1 g, 99% yield of formamide A as a colorless oil. GC/MS showed the product to be 100.0% pure and was used in the following step without further purification.
  • the formamide A (1.1 g, 4.0 mmol) was dissolved in dry THF (100 ml) and heated to reflux (no condenser) .
  • Borane- methyl sulfide complex (1.2 ml, 12 mmol, 10.5 M) was added dropwise over a period of 3 min to the refluxing solution. Reflux was maintained for approximately 15 min, open to the air, until the reaction volume was reduced to approximately 30 ml.
  • the reaction was then cooled in an ice bath, and ice (5 g, small pieces) was carefully added followed by H 2 0 (25 ml) and cone. HCI (25 ml) .
  • the acidic solution was refluxed for 30 min.
  • Compound 60 was synthesized from commercially available starting materials in the following four step reaction sequence.
  • the first intermediate in this synthetic route ethyl-N-benzyl-N- methyl-3-aminopropionate, was prepared by conjugate addition of N-benzylmethylamine to ethyl acrylate.
  • the ester functionality of the first intermediate was then reacted with two equivalents of Grignard reagent (prepared from l-bromo-3-fluorobenzene) to provide N-benzyl-N-methyl-3-hydroxy-3- (bis-3-fluorophenyl) propylamine.
  • Grignard reagent prepared from l-bromo-3-fluorobenzene
  • N-Benzyl-N-methyl-3-bis (3-fluorophenyl) allylamine hydrochloride (120.0 g, 0.311 mol) was dissolved in abs. EtOH (1250 mL) .
  • Pd (OH) 2 /charcoal (10.0 g, -20% Pd, Fluka
  • Compound 105 was prepared by selective reduction of its corresponding alkene by catalytic hydrogenation over Pd/C.
  • Compound 61 was prepared from 2-bromo-4- fluoroanisole and 3-fluorobenzaldehyde as described for Compound 24.
  • Compound 62 was prepared from 2-bromoanisole and 2- methoxybenzaldehyde as described for Compound 24.
  • the ketone A was synthesized similarly to ketone B in the Compound 24 synthesis using 2-methylphenyl-magnesium bromide and 2-methylbenzaldehyde as starting materials. This ketone was converted to the final product using the procedure outlined for Compound 58.
  • Compound 119 was synthesized in a seven-step reaction sequence starting from commercially-available trans-3- fluorocinnamic acid. This synthetic route is conceptually similar to that reported in the literature [U.S. Patent 4,313,896 (1982)] for related analogs. However, the three final steps were performed using a significantly different reaction sequence than that reported. The cinnamic acid was reduced and chlorinated in three steps to the corresponding 3- (3-fluorophenyl) propylchloride. This compound was
  • Compound 113 was synthesized from commercially available 4, 4-diphenylcyclohexenone in three steps. First, the alkene in the starting material was reduced by means of catalytic hydrogenation. Methoxylamine formation followed by reduction using standard procedures.
  • the enantiomers of Compound 136 were separated by analytical chiral HPLC. Aliquots (20 ⁇ g) were injected onto a Chiralcel-OD-R (Chiral Technologies, Inc., Exton, PA) reversed-phase HPLC column (0.46 x 250 mm) using the following conditions: gradient elution, 40%-70% ACN (60- 30% 0 . 5N KTFA) over 30 min; flow rate, 1 mL/min; detector, 264 nm. Two identically-sized peaks were collected at 21.0 and 24.4 min. GC/MS analysis of the two samples indicate that both materials have identical GC retention times as well as identical mass spectra.
  • reaction mixture was then poured into diethyl ether (200 mL) and the resulting suspension was centrifuged to remove the titanium precipitate. The supernatant was collected and the pellet was rinsed with diethyl ether (200 mL) . The combined organic washings were evaporated under vacuum to give a crude oil which was chromatographed on silica gel (elution with 4% MeOH-CH 2 Cl 2 ) to provide 647 mg (38%) of product.
  • the aqueous layer was neutralized (pR 7) by the careful addition of ION ⁇ aOH (14 mL) . Satd. aq. ⁇ aHC0 3 (50 mL) was added along with Et 2 0 (100 mL) and EtOAc (20 mL) . This mixture was shaken vigorously and the organic layer was separated. The aqueous layer was extracted with EtOAc (20 mL) . The combined organic layers were dried (anh. Na 2 S0 4 ) and rotary evaporated. The resulting oil was dissolved in EtOH, 1.0M HCI in Et 2 0 (7 mL) was added, and the solution was rotary evaporated.
  • aqueous layer was then neutralized (pH 7) by the careful addition of ION ⁇ aOH ("7 mL) . Satd. aq. ⁇ aHC0 3 (25 mL) was added along with Et 2 0 (50 mL) , EtOAc (15 mL) , and CHC1 3 (5 mL) . This mixture was shaken vigorously, and the organic layer was separated, dried (anh. Na 2 S0 4 ) , and filtered through paper. The crude product was then purified by RP- HPLC (20-60% acetonitrile-0.1% aq. HCI gradient over 20 min) . The fractions were frozen and lyophilized to afford 602 mg of product as a white solid.

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Abstract

Cette invention se rapporte à un procédé et à des compositions permettant de traiter un patient souffrant d'une maladie ou d'un trouble neurologique, tel que ictus, traumatisme crânien, lésion de la colonne vertébrale, ischémie de la colonne vertébrale, détérioration des cellules nerveuses induite par une ischémie ou une hypoxie, épilepsie, anxiété, déficits neuropsychiatriques ou cognitifs dus à une ischémie ou une hypoxie, tels que ceux qui se produisent fréquemment à la suite d'une chirurgie cardiaque sous pontage cardio-pulmonaire, ou maladies neurodégénératives, telles que la maladie d'Alzheimer, la maladie de Huntington, la maladie de Parkinson ou la sclérose latérale amyotrophique (ALS).
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US8906345B2 (en) 2006-09-20 2014-12-09 Isis Innovation Limited Multimeric particles
US11358971B2 (en) 2019-07-03 2022-06-14 H. Lundbeck A/S Prodrugs of modulators of the NMDA receptor
US11466027B2 (en) 2019-07-03 2022-10-11 H. Lundbeck A/S Modulators of the NMDA receptor

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