Methods and Compositions for Treating Thalamocortical Dysrhythmia

Abstract

This invention relates to methods of inhibiting a Ca v 3 calcium channel in a cell using a C 2 -C 10 alkyl alcohol, or mixtures thereof. This invention further relates to methods of treating a thalamocortical dysrhythmia disorder in a mammal and for treating a neurological disorder in a mammal associated with the thalamocortical dysrhythmia using a C 2 -C 10 alkyl alcohol, a lipophilic molecule with a partition coefficient substantially similar to that of a C 2 -C 10 alkyl alcohol, or mixtures thereof, or a pharmaceutical composition comprising the same.

1 . A method of reducing a low-threshold-activated calcium current in a cell by having a Ca v 3 plasmalemmal-bound calcium channel, the method comprising superfusing the extracellular environment of the cell with a C 2 -C 10  alkyl alcohol, or mixtures thereof, in an amount sufficient to modify the voltage-dependent activation kinetics or single channel ionic conductance of the Ca v 3 calcium channel, thereby reducing the low-threshold-activated calcium current in the cell. 
     
     
         2 . The method of  claim 1 , wherein the cell is in a mammal in need of inhibiting a Ca v 3 calcium channel. 
     
     
         3 . The method of  claim 1 , wherein the cell is a neuron, an interneuron, a projection thalamic neuron, a reticular thalamic neuron, a cortical interneuron, cortical pyramidal neuron, a basal ganglion neuron, a hippocampus neuron, an amygdala neuron, a tectal neuron, or a cerebellar neuron. 
     
     
         4 . The method of  claim 1 , wherein the Ca v 3 calcium channel is selected from the group consisting of a Ca v 3.1 calcium channel, a Ca v 3.2 calcium channel, a Ca v 3.3 calcium channel, and combinations thereof. 
     
     
         5 . The method of  claim 1 , wherein the C 2 -C 10  alkyl alcohol is administered in a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         6 . The method of  claim 1 , wherein the C 2 -C 10  alkyl alcohol is present in the extracellular environment at a concentration of from about 10 μM to about 100 μM. 
     
     
         7 . A method of inhibiting a Ca v 3 plasmalemmal-bound calcium channel in a cell, the method comprising administering to the mammal a C 2 -C 10  alkyl alcohol, or mixtures thereof, at a dose of from about 0.001 mg/kg body weight to about 20 mg/kg body weight of the mammal, the alcohol modifying the voltage dependent activation kinetics or single channels ionic conductance of the Ca v 3 calcium channel, thereby inhibiting the Ca v 3 calcium channel. 
     
     
         8 . The method of  claim 7 , wherein the alcohol is administered orally. 
     
     
         9 . The method of  claim 7 , wherein the alcohol is administered parenterally. 
     
     
         10 . The method of  claim 7 , wherein the C 2 -C 10  alkyl alcohol is 1-octanol. 
     
     
         11 . The method of  claim 7 , wherein the C 2 -C 10  alkyl alcohol is 2-octanol. 
     
     
         12 . The method of  claim 7 , wherein the mammal has a thalamocortical dysrhythmia disorder. 
     
     
         13 . A method of treating a neurological disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a Ca v 3 calcium channel inhibitor, provided that the neurological disorder is not tremor or Parkinson's tremor. 
     
     
         14 . A method of treating a thalamocortical dysrhythmia disorder that is not tremor or Parkinson's tremor in a mammal in need thereof, the method comprising administrating to the mammal a therapeutically effective amount of a Ca v 3 calcium channel inhibitor wherein the inhibitor binds to the Ca v 3 calcium channel, thereby reducing a low voltage-activated calcium current in the cell of the mammal. 
     
     
         15 . The method of  claim 14 , wherein the Ca v 3 calcium channel inhibitor is a C 2 -C 10  alkyl alcohol, or mixtures thereof. 
     
     
         16 . The method of  claim 14 , wherein the Ca v 3 calcium channel inhibitor is a lipophilic molecule with a partition coefficient substantially similar to that of a C 2 -C 10  alkyl alcohol. 
     
     
         17 . The method of  claim 14 , wherein the Ca v 3 calcium channel inhibitor is a lipophilic molecule with a partition coefficient substantially similar to that of an octanol. 
     
     
         18 . The method of  claim 14 , wherein the Ca v 3 calcium channel inhibitor is a lipophilic molecule with a molecular weight less than about 160. 
     
     
         19 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is petit mal epilepsy. 
     
     
         20 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is tinnitus. 
     
     
         21 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is neurogenic pain. 
     
     
         22 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is obsessive-compulsive disorder. 
     
     
         23 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is Tourettes disease. 
     
     
         24 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is chronic depression. 
     
     
         25 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is autism or Asperger's syndrome. 
     
     
         26 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is schizoaffective psychosis. 
     
     
         27 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is Parkinson's disorder. 
     
     
         28 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is Migraine. 
     
     
         29 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is Absence Epilepsy. 
     
     
         30 . The method of  claim 14 , wherein the thalamocortical dysrhythmia disorder is restless legs syndrome. 
     
     
         31 . The method of  claim 14 , wherein the C 2 -C 10  alkyl alcohol is administered in a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         32 . The method of  claim 14 , wherein the therapeutically effective amount administered is from about 0.001 mg/kg body weight to about 20 mg/kg body weight of the mammal. 
     
     
         33 . The method of  claim 14 , wherein the therapeutically effective amount administered is from about 0.1 mg/kg body weight to about 10 mg/kg body weight of the mammal. 
     
     
         34 . The method of  claim 33 , wherein the therapeutically effective amount administered is from about 0.3 mg/kg body weight to about 3.0 mg/kg body weight of the mammal. 
     
     
         35 . The method of  claim 33 , wherein the therapeutically effective amount administered is about 1.0 mg/kg body weight of the mammal. 
     
     
         36 . The method of  claim 14 , wherein the alcohol is administered orally. 
     
     
         37 . The method of  claim 14 , wherein the alcohol is administered parenterally. 
     
     
         38 . The method of  claim 14 , wherein the C 2 -C 10  alkyl alcohol is selected from the group consisting of
 (a) CH 3 —(CH 2 ) n —OH, wherein n is an integer from 1 to 9,   (b) CH 3 —CH(OH)—(CH 2 ) m —CH 3 , wherein m is an integer from 0 to 7,   (c) CH 3 —CH 2 —CH(OH)—(CH 2 ) p —CH 3 , wherein p is an integer from 0 to 6,   (d) CH 3 —CH 2 —CH 2 —CH(OH)—(CH 2 ) q —CH 3 , wherein q is an integer from 0 to 5,   (e) CH 3 —CH 2 —CH 2 —CH 2 —CH(OH)—(CH 2 ) w —CH 3 , wherein w is an integer from 0 to 4, and   (f) mixtures thereof.   
     
     
         39 . The method of  claim 14 , wherein the C 2 -C 10  alkyl alcohol is 1-octanol. 
     
     
         40 . The method of  claim 14 , wherein the C 2 -C 10  alkyl alcohol is 2-octanol. 
     
     
         41 . A method for identifying an alkyl alcohol that modifies the voltage-dependent activation kinetics or single channel ionic conductance of a Ca v 3 plasmalemmal-bound calcium channel protein, the method comprising:
 (a) providing atomic coordinates of the Ca v 3 calcium channel protein;   (b) subjecting an alkyl alcohol to computational molecular docking; and   (c) selecting the alcohol that has the optimal virtual binding to the a Ca v 3 calcium channel protein,   the optimal virtual binding indicating that the alcohol binds to the a Ca v 3 calcium channel protein or alters the properties of the lipid bi-layer at the channel's voltage sensing site.   
     
     
         42 . The method of  claim 41 , wherein the computational molecular docking utilizes a computer screening method selected from the group consisting of Virtual library screening (VLS), ICM, ICM-VLS, DOCK, and FlexX. 
     
     
         43 . A method of identifying a chemical entity which binds to a Ca v 3 calcium channel, the method comprising comparing a structure model of the Ca v 3 calcium channel with a structure model for the chemical entity, and detecting (i) a binding surface on the Ca v 3 calcium channel for the chemical entity, or (ii) an alteration of the properties of the lipid bi-layer at the channel's voltage sensing site for the chemical entity. 
     
     
         44 . The method of  claim 43 , wherein the structural model of the Ca v 3 calcium channel is derived from a structure-predicting algorithm. 
     
     
         45 . The method of  claim 43 , wherein the Ca v 3 calcium channel is selected from the group consisting of a Ca v 3.1 calcium channel, a Ca v 3.2 calcium channel, a Ca v 3.3 calcium channel, and combinations thereof. 
     
     
         46 . The method of  claim 43 , wherein the structure model of the Ca v 3 calcium channel is derived from atomic coordinates determined by subjecting a crystal comprising a Ca v 3 calcium channel to X-ray diffraction measurements. 
     
     
         47 . A method of identifying an inhibitor of a Ca v 3 calcium channel in a cell, the method comprising:
 contacting an isolated Ca v 3 plasmalemmal-bound calcium channel with a candidate compound; and detecting the presence of a complex, or lack thereof, between the Ca v 3 calcium channel and the compound,   the candidate compound being an inhibitor if it forms a complex with the Ca v 3 calcium channel or alters the properties of the lipid bi-layer at the channel's voltage sensing site.   
     
     
         48 . A pharmaceutical composition comprising:
 a therapeutically effective amount of a C 2 -C 10  alkyl alcohol, or mixtures thereof; and at least one other therapeutic agent selected from the group consisting of: a barbiturate or barbituric acid derivative, an anesthetic agent, a tinnitus treating agent, a selective serotonin reuptake inhibitor, an antidepressant agent, a neuroleptic, an antihypertensive agent, a calcium channel blocker, and an ACE inhibitor, and combinations thereof.   
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein the C 2 -C 10  alkyl alcohol is 1-octanol. 
     
     
         50 . The pharmaceutical composition of  claim 48 , wherein the C 2 -C 10  alkyl alcohol is 2-octanol. 
     
     
         51 . The composition of  claim 48 , wherein the barbiturate or barbituric acid derivative is selected from the group consiting of sodium thiopental, pentobarbital, secobarbital, amobarbital, butabarbital, barbital, phenobarbital, butalbital, cyclobarbital, allobarbital, methylphenobarbital, secobarbital, vinylbital and methohexital. 
     
     
         52 . The composition of  claim 48 , wherein the anesthetic agent is selected from the group consisting of propofol, etomidate, isoflurane, halothane, and ketamine. 
     
     
         53 . The composition of  claim 48 , wherein the tinnitus-treating agent is selected from the group consisting of zinc supplementation, acamprosate, etidronate or sodium fluoride, lignocaine, carbemazepine, melatonin, sertraline and vitamin combinations. 
     
     
         54 . The composition of  claim 48 , wherein the selective serotonin reuptake inhibitor is selected from the group consisting of paroxetine, sertraline, fluoxetine and fluvoxamine. 
     
     
         55 . The composition of  claim 48 , wherein the antidepressant agent is selected from the group consisting of Harmaline, Iproniazid, Isocarboxazid, Moclobemide, Nialamide, Pargyline, Phenelzine, Toloxatone, Tranylcypromine, Brofaromine, Moclobemide, Amineptine, Phenmetrazine, Vanoxerine, Bupropion, Atomoxetine, Maprotiline, Reboxetine, Viloxazine, Duloxetine, Milnacipran, Nefazodone Venlafaxine, Alaproclate, Citalopram, Escitalopram, Etoperidone, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine, Tianeptine, Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Dibenzepin, Dothiepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Trimipramine, Maprotiline, Mianserin, Nefazodone, and Trazodone. 
     
     
         56 . The composition of  claim 48 , wherein the neuroleptic selected from the group consisting of risperidone, ziprasidone, haloperidol, pimozide and fluphenazine. 
     
     
         57 . The composition of  claim 48 , wherein the antihypertensive agent is selected from the group consisting of clonidine and guanfacine. 
     
     
         58 . The composition of  claim 48 , wherein the calcium channel blocker is selected from the group consisting of amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, verapamil, gallopamil, diltiazem, mibefradil, and menthol. 
     
     
         59 . The composition of  claim 48 , wherein the ACE inhibitor is selected from the group consisting of enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril and fosinopril. 
     
     
         60 . A method of treating a thalamocortical dysrhythmia disorder in a mammal in need thereof, the method comprising administrating to the mammal a therapeutically effective amount of a pharmaceutical composition comprising of a C 2 -C 10  alkyl alcohol, or mixtures thereof; and at least one other therapeutic agent. 
     
     
         61 . The method of  claim 60 , wherein the C 2 -C 10  alkyl alcohol is 1-octanol, 2-octanol or mixtures thereof, and wherein the at least one other therapeutic agent is selected from the group consisting of: anticonvulsant or antiepileptic agent, a barbiturate or barbituric acid derivative, an anesthetic agent, a tinnitus-treating agent, a selective serotonin reuptake inhibitor, an antidepressant agent, a neuroleptic, an antihypertensive agent, an antipsychotic agent, a calcium channel blocker, an ACE inhibitor, and a beta-blocker. 
     
     
         62 . A method of treating a neurological disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising of a C 2 -C 10  alkyl alcohol, or mixtures thereof, and at least one other therapeutic agent, wherein neurological disorder is not tremor or Parkinson's tremor. 
     
     
         63 . The method of  claim 62 , wherein the C 2 -C 10  alkyl alcohol is 1-octanol, 2-octanol or mixtures thereof, and wherein the at least one other therapeutic agent is selected from the group consisting of: anticonvulsant or antiepileptic agent, a barbiturate or barbituric acid derivative, an anesthetic agent, a tinnitus-treating agent, a selective serotonin reuptake inhibitor, an antidepressant agent, a neuroleptic, an antihypertensive agent, an antipsychotic agent, a calcium channel blocker, an ACE inhibitor, and a beta-blocker.