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Molecular Pharmacology

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Research ArticleArticle

Interaction of Barbiturate Analogs with the Torpedo californica Nicotinic Acetylcholine Receptor Ion Channel

Hugo R. Arias, Elizabeth A. McCardy, Martin J. Gallagher and Michael P. Blanton
Molecular Pharmacology September 2001, 60 (3) 497-506;
Hugo R. Arias
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Elizabeth A. McCardy
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Martin J. Gallagher
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Michael P. Blanton
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Abstract

Barbiturate-induced anesthesia is a complex mechanism that probably involves several ligand-gated ion channel superfamilies. One of these superfamilies includes the archetypical nicotinic acetylcholine receptor (nAChR), in which barbiturates act as noncompetitive antagonists. In this regard, we used the Torpedo californica nAChR and a series of barbiturate analogs to characterize the barbiturate binding site(s) on this superfamily member. [14C]Amobarbital binds to one high-affinity (Kd = 3.7 μM) and several (∼11) low-affinity (Kd = 930 μM) sites on the resting and desensitized nAChRs, respectively. Characteristics of the barbiturate binding site on the resting nAChR include: (1) a tight structure-activity relationship. For example, the barbiturate isobarbital [5-ethyl-5′-(2-methylbutyl) barbituric acid] is >10-fold less potent than its formula isomer amobarbital [5-ethyl-5′-(3-methylbutyl) barbituric acid] in inhibiting [14C]amobarbital binding. (2) A binding locus within the pore of the nAChR ion channel. Each of the barbiturate analogs inhibited the binding of [3H]tetracaine or photoincorporation of 3-trifluoromethyl-3-(m-[125I]iodophenyl) diazirine in a mutually exclusive manner. (3) Stereoselective binding. The R(+)-enantiomers of isobarbital and pentobarbital are ∼2-fold more potent in inhibiting 3-trifluoromethyl-3-(m-[125I]iodophenyl) diazirine photoincorporation than the S(−)-enantiomers. Finally, molecular modeling suggests that within the channel, the pyrimidine ring of the barbiturate is located just above the highly conserved leucine ring (M2–9; e.g., δLeu-265), whereas the 5′ side chain projects downward, and depending upon its conformation, introduces steric hindrance to binding because of the restriction in the lumen of the channel introduced by the leucine side chains.

Footnotes

  • This research was supported in part by National Institutes of Health Grant R29-NS35786 (M.P.B.).

  • Abbreviations:
    LGIC
    ligand-gated ion channel
    nAChR
    nicotinic acetylcholine receptor
    5-HT3R
    type 3 5-hydroxytryptamine receptor
    GABAAR
    type A γ-aminobutyric acid receptor
    NCA
    noncompetitive antagonist
    [125I]TID
    3-trifluoromethyl-3-(m-[125I]iodophenyl) diazirine
    [3H]TCP
    [piperidyl-3,4-3H (N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine
    PCP
    phencyclidine
    CCh
    carbamylcholine
    dansyltrimethylamine
    [1-(dimethylamino)-napthalene-5-sulfonamido]ethyltrimethylammonium perchlorate
    HPLC
    high-performance liquid chromatography
    amobarbital
    5-ethyl-5′-(3-methylbutyl) barbituric acid
    amylbarbital
    5-ethyl-5′-amyl barbituric acid
    isobarbital
    5-ethyl-5′-(2-methylbutyl) barbituric acid
    pentobarbital
    5-ethyl-5′-(1-methylbutyl) barbituric acid
    VDB
    vesicle dialysis buffer
    • Received March 21, 2001.
    • Accepted June 8, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Interaction of Barbiturate Analogs with the Torpedo californica Nicotinic Acetylcholine Receptor Ion Channel

Hugo R. Arias, Elizabeth A. McCardy, Martin J. Gallagher and Michael P. Blanton
Molecular Pharmacology September 1, 2001, 60 (3) 497-506;

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Research ArticleArticle

Interaction of Barbiturate Analogs with the Torpedo californica Nicotinic Acetylcholine Receptor Ion Channel

Hugo R. Arias, Elizabeth A. McCardy, Martin J. Gallagher and Michael P. Blanton
Molecular Pharmacology September 1, 2001, 60 (3) 497-506;
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