MAIN IONOTROPIC RECEPTORS (5x)

Table of contents :




 
name
expressed on ...
ligand(s)
agonists
antagonists
... whose ligands induce channel opening :

Ca2+ channels (also permeable to Na+ (1 Na+ every 5 Ca2+) and K+)

NMDA receptor (NMDAR) (heteromer:  Clathrin-dependent NMDAR endocytosis requires both Gly and Glu site activation. The NR1–NR2A heterodimer is the functional unit in tetrameric NMDA receptors and tyrosine 535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivationref hippocampus, neurons, myelinating processes of precursor, immature and mature oligodendrocytes in the white matter of the cerebellum and corpus callosumref (NR1, NR2A, NR2B, NR2C, NR2D and NR3A subunits showed clustered expression in cell processes, but NR3B was absentref)ref Glu + Gly

Asp + Gly

quinolinate 

taurine (antagonist)

NMDA + Gly

homoquinolinate 

D-cycloserine (DCS) (Seromycin®) (partial agonist)

broad-spectrum NMDA receptor antagonists :
  • 7-chlorokynurenic acid
  • noncompetitive antagonists : 
  • competitive antagonists : 
    • D-AP-5 / (+/-)-2-amino-5-phosphonovaleric acid (APV)
    • D-AP-7 (partial agonist)
    • (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP)
    • a-methyl-carboxyphenylglycine
    • amantadine (Symmetrel®)
    • memantadine
    • memantine (Axura®, Akatinol®, Exiba®, Namenda®, Neuroplus®)
    • riluzole / 2-amino-6-[trifluoromethoxy]benzothiazole (Rilutek®)
    • metapramine (Timaxil®)
    • ketanserin (Sufrexal®, Aseranox®, Ketensin®, Ketenserina®, Perketan®, Serepress®, Sparfloxacine®)
antagonists at the polyamine site (blockers of NR2A and NR2B subunit-containing receptors) : 
  • eliprodil
  • ifenprodil
  • NVP-AAM0775
drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions 
  • 619C89
  • lubeluzole (Prosynap®) is a benzothiazole derivative that has shown neuroprotective properties in different experimental models inhibiting glutamate release, nitric oxide (NO) synthesis and blocking voltage-gated Na+ and Ca2+ ion channels
competitive antagonists of the glutamate recognition site of the NMDA receptor 
  • selfotel
noncompetitive blockers of the ion channel associated with the NMDA receptor : 
  • aptiganel (Cerestat®)
competitive antagonists of the glycine recognition site : 
  • ACEA 1021
  • GV150526
  • gavestinel
  • SDZ EAA 494 (D-CPP-ene) 
  • Na+ and K+ channels (also permeable to Ca2+)
    kainate (heteromer : subunits 1, 2, 3, 4 and 5 B lymphocytes Glu kainic acid 
    domoic acid
    AP5 
    MK801 
    LY223053 
    riluzole / 2-amino-6-[trifluoromethoxy]benzothiazole (Rilutek®)
    AMPA receptor (AMPAR) (heteromer : subunits  granule and pyramidal cells in the hippocampal formation : active only upon depolarization (often mediated by AMPA receptors) and Gly costimulation Glu
  • a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) 
  • 1,4-dihydroquinoxaline-2,3-dione (ANQX) (obtained from DNQX by replacing one of the nitro groups (NO2) with a highly photoreactive azido group (-N3); upon exposure to UV light, the azido group loses dinitrogen (-N2) to form a nighly reactive nitrene (:N), and this photoactivated antagonist then irreversibly binds to and inhibits AMPARsref)
  • quisqualic acid
  • 6-cyano-7-nitroquinoxaline 
    -2,3-dione (CNQX) 
    LY215490 
    barbiturates (also GABAA agonists) 
    • 2-oxybarbiturates
      • long-acting barbiturates (5-phenyl substituent; anticonvulsant acitivity)
        • barbital (Barbital®, Calmine®, Neurinase®, Peralga®, Plexonal®, Veramon®, Veronal®)
        • mephobarbital (Mebaral®)
        • primidone (Mysoline®) => phenobarbital (PB) (also CAR agonist) (Adonal®, Alepsal®, Anirrit®, Barecal®, Corosedine®, Deriminal®, Dilatrane®, Dolviran®, Epanal®, Eupaco®, Gardenal®, Gardenale®, Hydantal®, Luminal®, Luminalettes®, Myocardon®, Natisedine®, Nunol®, Perphyllon®, Phenobarbital®, Plexonal®, Priscophene®, Quietal®, Tensedine®, Solfoton®, ..) and phenylethylmalonamide (PEMA)
        • methylphenobarbital (Prominal®)
      • medium-acting barbiturates
        • amobarbital (Amesec®, Amytal®, Dexamyl®, Eunoctal®, Tuinal®)
        • cyclobarbital (Cyclobartital®, Phanodorme®, Phanodorme calcium®, Proponal®, Quadronox®, Sanox®)
        • heptabarbital (Medomine®)
      • short-acting barbiturates
        • butabarbital / butobarbital (Butisol®)
        • hexobarbital (Evipan®, Tobinal®)
        • pentobarbital (Barecal®, Carbrital®, Nembutal®)
        • secobarbital (Immenoctal®, Secorbarbital®, Seconal®, Tuinal®; Vesparax® in combination with hydroxyzine and brallobarbital)
      • ultra-short acting barbiturates
        • methohexital (Brevital®)
      • allobarbital (Asmac®, Cibalgine®, Dial®, Somnocodal®)
      • alphenal (Efrodal®)
      • aprobarbital (Alurate®, Plexonal®, Somnifene®)
      • brallobarbital (Vesparax® in combination with  hydroxyzine and secobarbital)
      • cyclopentobarbital (Barecal®, Cyclopal®)
      • phethabarbital / N-phenylbarbital
      • propylbarbital (Proponal®)
      • talbutal
      • tetralobarbital (Sandoptal®)
    • 2-thiobarbiturates (more lipid-soluble => decreased duration of action, latency to onset, accelerated degradation)
      • thiamylal (Surital®)
      • thiopental sodium (Pentothal®; "Truth serum")
    5-HT3 / M receptor (heterodimer : a and b subunits) chemo-receptor trigger zone (CTZ; area postrema) ; 
    stomach ; 
    small intestine ; 
    nucleus tractus solitarius (NTS) ; peripheral nerves
    5-HT a-methyl-5-HT 
    m-chlorophenylpiperazine (mCPP) 
    metoclopramide (Plasil®, Reglan®
    alosetron (Lotronex®
    dolasetron / hydroxydolasetron (Anzemet®
    granisetron (Kytril®
    ondansetron (Zofran®, Zophren®) ; ondansetron orally disintegrating tablets (ODT) 
    palonosetron (Aloxi® : > 30X higher affinity, half-life = 40 hours, single 0.25 mg IV dose) 
    tropisetron (Navoban®
    mianserin (Norval®)
    P2X1 (homo-trimer: it can heterodimerize with P2X5) B lymphocytes, urinary bladder alpha,beta-methyleneATP suramin
    PPADS
    P2X2 (homo-trimer : it can heterodimerize with P2X3) B lymphocytes alpha,beta-methyleneATP suramin
    PPADS
    P2X3 (homo-trimer: it can heterodimerize with P2X2) heart, spinal cord alpha,beta-methyleneATP suramin
    PPADS
    P2X4 (homo-trimer: it can heterodimerize with P2X6) B lymphocytes, brain alpha,beta-methyleneATP suramin
    PPADS
    P2X5 (homo-trimer : it can heterodimerize with P2X1) activated T-cells alpha,beta-methyleneATP suramin
    PPADS
    P2X6 (homo-trimer: it can heterodimerize with P2X4) placenta, spleen alpha,beta-methyleneATP suramin
    PPADS
    P2X7 / P2Z (homo-trimer) : upon brief exposure to ATP in the mM range, P2X7 functions as a nonselective cation channel, but upon prolonged exposure, channels rapidly transform into pores allowing passages of solutes up to 800 Da, leading to cell death by apoptosis. B lymphocytes alpha,beta-methyleneATP suramin
    PPADS
    OxATP
    salt molecules tongue
    Na+ channels (also permeable to K+, Ca2+, Rb+, Mg2+ and NH4+)
    • a 
    • b 
    • d
    • e 
    • g

    •  
    • skeletal muscle (NM) : 
      • (a1)2b1gd
      • (a1)2b2ed
    • postsynaptic neurons of autonomic ganglia and adrenal medulla (NN) : (a2-9)2(b2-4)3
    • NCNS : (a2-9)0-5(b2-4)5-0
    skeletal muscle cells, 
    postganglionic neurons in both 
    ortosympathetic and parasymphatetic systems, bronchial epithelial and endothelial cells, 
    electroplaque of Electrophorus spp. and Torpedo spp..
    ACh homoanatoxin-a
    anatoxin-a
    a-conotoxin
    epibatidine
    partial agonists :
    • cytisine (naturally occurring plant alkaloid, a partial agonist at the a4b2
    • varenicline tartrate (Chantix® in the USA and Champix® in Europe; source : Pfizer) (greatly improved penetration in the CNS)
    ganglionic stimulating drugs
    • nicotine (polacrilex gums (Nicorette®), trandermal patch (Nicoderm®, Habitrol®, ...), nasal spray (Nicotrol NS®), and vapor inhaler (Nicotrol Inhaler®))
    • lobeline
    • tetramethylammonium (TMA)
    • phenyltrimethylammonium (PTMA)
    • 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP)
     
    Me-lycaconitine 
    ganglioplegics / ganglionic blocking agents
    • tetraetylammonium (TEA)
    • hexamethonium (C6)
    • trimethaphan (Arfonad®)
    • mecamylamine (Inversine®, Mevasine®, Prexion®)
    neuromuscular blocking agents
    • depolarizing agents
      • decamethonium (C10)
      • succinylcholine (Anectine®, ...)
      • suxamethonium (Scoline®)
    • competitive (stabilizing) agents
    Cl- channels
    GABAA receptor complex (GRC) : a2b2g presynaptic in spinal cord a-motoneurons; postsynaptic in cortical and cerebellar pyramidal cells, cuneate nucleus, substantia nigra, and thalamic relay neurons GABA (a subunit) 

    endozepin-4 (b subunit) 

    taurine

    pagoclone (partial agonist/modulator
    benzodiazepines (BDZ) (allosteric drugs on b subunit; binding requires g subunit, too) 
    • 2-ketobenzodiazepines (active catabolites)
      • short half-life
        • bromazepam (Lectopam®, Lexotan®, Lexotanil®)
      • long half-life (t > 40 hrs)
        • chlordiazepoxide (Librax®, Libritabs®,  Librium®, Tropium®; Limbitrol® in combination with amitriptyline)
        • chlordesmethyldiazepam / delorazepam (En®)
        • clobazam (Frisium®)
        • clorazepate (Tranxene®, Tranxilene®)
        • diazepam (DZP) (Dizac®, Noan®, Valium®)
        • flurazepam (Flunox®, Dalmane®)
        • halazepam (Paxipam®, Alapryl®, Pacinone®)
        • ketazolam (Anxon®)
        • medazepam (Nobrium®, Debrun®, Lerisum®, Rusedal®)
        • pinazepam (Domar®)
        • prazepam (Centrax®)
        • quazepam (Dormalin®, Doral®, Prosedar®, Quazium®, Selepam®, Temodal®)
    • 3-hydroxybenzodiazepines (t < 24 hrs)
      • comazepam
      • lorazepam (Ativan®, Tavor®, Alzapam®, Almazine®, Durazolam®, Loraz®, Temesta®)
      • lormetazepam (Noctamid®, Noctamide®, Ergocalm®)
      • oxazepam (Serenid®, Serpax®, Serax®, Adumbran®, Alepam®, Murelax®, Serepax®, Seresta®, Vaben®
      • temazepam (Eupnios®, Restoril®)
    • 7-nitrobenzodiazepines (24 < t < 48 hrs)
      • clonazepam (CZP) (Rivotril®, Klonopin®)
      • flunitrazepam (Hipnosedon®, Roipnol®, Rohypnol®) (drug of abuse)
      • nitrazepam (Mogadon®)
    • triazolobenzodiazepine (2 < t < 5 hrs)
      • adinazolam (Deracyn®)
      • alprazolam (Ansiopax®, Apotex®, Constan®, Mialin®, Pazolam®, Tafil®, Tranquinal®, Xanax®, Xanor®, Zanapam®)
      • estazolam (Prosom®, DEprinocte®, Domnamid®, Esilgan®, Kainever®, Nuctalon®
      • midazolam (Versed®, Dormicum®, Hypnovel®
      • triazolam (Halcion®, Songar®, Triazoral®, Alpralid®)
    • thienodiazepines (t > 24 hrs)
      • brotizolam (Lendormin®)
      • clotiazepam
    • loprazolam (Dormonoct®, Havlane®, Sonan®)
    • metaclazepam (Talis®)
    imidazopyridines
    • alpidem (Anaxyl®)
    • zolpidem (Stilnox®, Ambien®)
    pyrazolopyrimidine
    • zaleplon (Sonata®)
    imidazopyrimidines
    imidazoquinolones
    cyclopyrrolones
    • eszopiclone (Lunesta®)
    • zopiclone (Imovane®, Rhovane®, Zimovane®)
    barbiturates (complete agonists ; also AMPAR antagonists) 
    • 2-oxybarbiturates
      • long-acting barbiturates (5-phenyl substituent; anticonvulsant acitivity)
        • barbital (Barbital®, Calmine®, Neurinase®, Peralga®, Plexonal®, Veramon®, Veronal®)
        • mephobarbital (Mebaral®)
        • primidone (Mysoline®) => phenobarbital (also CAR agonist) (Adonal®, Alepsal®, Anirrit®, Barecal®, Corosedine®, Deriminal®, Dilatrane®, Dolviran®, Epanal®, Eupaco®, Gardenal®, Gardenale®, Hydantal®, Luminal®, Luminalettes®, Myocardon®, Natisedine®, Nunol®, Perphyllon®, Phenobarbital®, Plexonal®, Priscophene®, Quietal®, Tensedine®, Solfoton®, ..) and phenylethylmalonamide (PEMA)
        • methylphenobarbital (Prominal®)
      • medium-acting barbiturates
        • amobarbital (Amesec®, Amytal®, Dexamyl®, Eunoctal®, Tuinal®)
        • cyclobarbital (Cyclobartital®, Phanodorme®, Phanodorme calcium®, Proponal®, Quadronox®, Sanox®)
        • heptabarbital (Medomine®)
      • short-acting barbiturates
        • butabarbital / butobarbital (Butisol®)
        • hexobarbital (Evipan®, Tobinal®)
        • pentobarbital (Barecal®, Carbrital®, Nembutal®)
        • secobarbital (Immenoctal®, Secorbarbital®, Seconal®, Tuinal®; Vesparax® in combination with hydroxyzine and brallobarbital)
      • ultra-short acting barbiturates
        • methohexital (Brevital®)
      • allobarbital (Asmac®, Cibalgine®, Dial®, Somnocodal®)
      • alphenal (Efrodal®)
      • aprobarbital (Alurate®, Plexonal®, Somnifene®)
      • brallobarbital (Vesparax® in combination with  hydroxyzine and secobarbital)
      • cyclopentobarbital (Barecal®, Cyclopal®)
      • phethabarbital / N-phenylbarbital
      • propylbarbital (Proponal®)
      • talbutal
      • tetralobarbital (Cafergot®, Sandoptal®)
    • 2-thiobarbiturates (more lipid-soluble => decreased duration of action, latency to onset, accelerated degradation)
      • thiamylal (Surital®)
      • thiopental sodium (Pentothal®; "Truth serum")
    muscimol
    isoguvacine 
    THIP 
    halothane (Fluothane®
    enflurane (Ethrane®
    isoflurane (Forane®
    desflurane (Suprane®
    methoxyfluorane (Metofane®
    sevoflurane (Ultane®
    nitrous oxide / dinitrogen monoxide / N2
    propofol (Diprivan®
    etomidate (Amidate®
    neurosteroids : carbamates 
    • carisoprodol (Soma®) => meprobamate (Eubamate®, Meprobamatum®, Meprocalm®, Meprodil®, Meprolettes®, Miltown®, Oasil®, Pertranquil®, Probamyl®, Proponal®, Quaname®, Equanil®, Meprotabs®, Meprospan®, Meptran®, Novalm®, Promate®, Vio-Bamate®)
    chloral hydrate => trichloroethanol (CCl3CH2OH) 
    paraldehyde (Paral®
    ethchlorvynol (Placidyl®
    glutethimide (Doridene®, Ondasil®
    methyrprylon 
    ethinamate 
    etomidate (Amidate®
    clomethiazole 
    compound 4 (a2 subunit selectivity => anxiolytic activity without sedative liability)
    b-carbolines (inverse agonists) ; 
    RO 15-4513 (inverse agonist on a6-containing GABAA
    SR 95531 
    bicucullin 
    picrotoxin
    pentamethylentetrazole 
    imidazobenzodiazepine 
    • flumazenil (Romazicon®)
    chlorinated cyclodiene insecticides : 
    • aldrin
    • chlordane
    • dieldrin
    • endrin
    • heptachlor
    hexachlorocyclohexane (HCH) / benzene hexachloride (BHC) is a mixture of 8 isomers 
    • CNS-stimulating isomers
      • a isomer
      • g isomer / lindane
    • CNS-depressing isomers
      • b isomer
      • d isomer
    • e
    • z / i
    • h
    • q
  • toxaphene is a complex mixture of > 175 C10 polychlorinated hydrocarbons, of which only ~ 20 are known (e.g. heptachlorobornane)
  • mirex
  • chlordecone (Kepone®)
  • tetramine (tetramethylene disulfotetramine)
  • fluoroquinolones
  • GABACref retina, spinal cord, superior colliculus, pituitary and the gut and their involvement in vision, aspects of memory and sleep-waking behaviour GABA partial agonists :
    •  (+/-)-trans-2-(aminomethyl)cyclopropanoic acid ((+/-)-TAMP) and imidazole-4-acetic acid (I4AA) 
    • CACA
    P4PMA
    1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA)
    4,5,6,7-tetrahydroisoxazole[4,5-c]pyridine-3-ol (THIP)
    2-methyl-TACA 
    picrotoxin
    Zn2+ > Ni2+ > Cu2+ > Cd2+ref
    Gly (heterodimer :  Gly
    taurine
    b-alanine 
    D-serine 

    halothane (Fluothane®
    enflurane (Ethrane®
    isoflurane (Forane®
    desflurane (Suprane®
    sevoflurane (Ultane®
    nitrous oxide / dinitrogen monoxide / N2
    propofol (Diprivan®
    barbiturates
    neurosteroids 

    • alphaxalone (Althesin®)
    • pregnanolone
    strychnine
    H+ channels
    acidic molecules tongue
    ... whose ligands induce channel closing :

    K+ channels

    some bitter molecules tongue
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