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Research ArticleMinireview—A Latin American Perspective On G Protein-Coupled Receptors

The Histamine H3 Receptor: Structure, Pharmacology, and Function

Gustavo Nieto-Alamilla, Ricardo Márquez-Gómez, Ana-Maricela García-Gálvez, Guadalupe-Elide Morales-Figueroa and José-Antonio Arias-Montaño
Molecular Pharmacology November 2016, 90 (5) 649-673; DOI: https://doi.org/10.1124/mol.116.104752
Gustavo Nieto-Alamilla
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
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Ricardo Márquez-Gómez
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
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Ana-Maricela García-Gálvez
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
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Guadalupe-Elide Morales-Figueroa
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
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José-Antonio Arias-Montaño
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
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  • Figure1
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  • Fig. 1.
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    Fig. 1.

    The histaminergic system in the rat brain. Histamine-synthesizing neurons are located in the hypothalamus tuberomamillary nucleus, and these neurons send projections to the CNS through three major pathways, two ascending bundles that innervate the forebrain structures, and one descending bundle reaching the spinal cord. Thal, thalamus; Str, striatum.

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    Fig. 2.

    Alignment of the amino acid sequence of the human, monkey, guinea pig, rat, and mouse H3Rs. Sequences were obtained from Uniprot (Washington, DC) and correspond to the full-length H3R (445 aa). Alignment was performed with the Clustal Omega server from the European Bioinformatic Institute (Cambridge, UK). The highly conserved sequences in the seven transmembrane domains are shown in gray. The DRF and NPVLY motifs and the glycosylation site (Asn11) are well conserved among species (green). Residues in blue are responsible for the interspecies differences in H3R pharmacology. Residues in red are likely to be involved in the receptor high constitutive activity on the basis of their identity with a mutated β2-adrenoceptor. The third intracellular loop (ICL3) possesses a region (residues 236–300; italics) that is highly variable among species, followed by a highly conserved sequence. The hH3R has ≥93% sequence identity with the other species, and the same identity can be found in guinea pig, mouse, and rat sequences, with 99% identity between mouse and rat, and among the primate proteins. *, conserved residues; :, conservative mutations; •, nonconservative mutations.

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    Fig. 3.

    Structure of the human H3R. As a GPCR, the H3R contains seven spanning transmembrane domains, an extracellular amino terminus (NT), an intracellular carboxyl terminus (CT), three extracellular (ECL), and three intracellular (ICL) loops, with a long ICL3 (142 aa). Potential residues for phosphorylation are shown in green. The conserved DRF and NPVLY motifs are shown in yellow. The naturally occurring mutations D18E and A280V are depicted in blue. The glycosylation site (Asn11) is shown in red, the palmitoylation site (C228) in gray. Residues Thr119 and Ala122 (purple) are responsible for the interspecies pharmacologic differences. Residues indicated in black in ECL1 and ECL2 correspond to the cysteins forming a disulfide bond important for receptor trafficking. Residues important for agonist recognition are colored in pink.

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    Fig. 4.

    H3R signaling pathways. H3R activation triggers or modulates several pathways through the Gα subunits and Gβγ complexes of Gαi/o proteins. AA, arachidonic acid; AC, adenylyl cyclases; cAMP, 3′,5′-cyclic adenosine monophosphate; MAPK, mitogen-activated protein kinases; NHE, Na+/H+ exchanger; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PLA2, phosholipase A2; PLC, phosholipase C.

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    Fig. 5.

    Binding sites of agonists and antagonists at the human H3R of 445 aa (hH3R445). (A) Molecular docking of the endogenous agonist histamine in a model of the hH3R445 in the active state. Residues Glu206 and Asp114 are pivotal for agonist binding. (B) Planar view of the histamine binding pocket in the hH3R445. (C) Proposed binding site of a protean ligand (proxyfan) in the inactive hH3R445 as observed by molecular docking, depicting the three functional groups of the ligand important for binding (nitrogen-containing ring, central electronegative group and aromatic ring). (D) Planar view of the suggested binding residues for an antagonist at the hH3R445.

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    Fig. 6.

    Structure of H3R agonists.

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    Fig. 7.

    Structure of H3R antagonists.

Tables

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    TABLE 1

    Brain expression and signaling of H3R isoforms from different species

    The human H3R329a and H3R329b isoforms possess the same number of amino acids but differ in the region where alternative splicing occurs.

    SpeciesIsoform (aa)Expression in the Central Nervous SystemSignalingReferences
    HumanH3(445)Thalamus, striatum, cerebral cortex, cerebellum, amygdala, substantia nigra, hippocampus, hypothalamus, corpus callosum, spinal cord↓ cAMP, ↑ [Ca2+]iLovenberg et al., 1999; Nakamura et al., 2000; Cogé et al., 2001; Tardivel-Lacombe et al., 2001; Tsui, 2001; Wiedemann et al., 2002; Wellendorph et al., 2002; Gallagher and Yates, 2007; Bongers et al., 2007a,b
    ↑ p42/p44-MAPK,
    ↑ [35S]-GTPγS binding
    H3(431)Amygdala, cerebellum, striatum, thalamus, prefrontal cortex, striatum,ND
    H3(415)Thalamus, cerebellum, amygdala↑ [Ca2+]i
    H3(365)Cerebellum, thalamus, hypothalamus, striatum, substantia nigra, hippocampus, amygdala, prefrontal cortex↑ [Ca2+]i, ↓ cAMP,
    ↑ [35S]-GTPγS binding
    H3(329a)Substantia nigra, amygdala, cerebral cortex, hypothalamusNF
    H3(326)Substantia nigra, prefrontal cortex, amygdala, hypothalamusND
    H3(413)Striatum, amygdalaND
    H3(453)ND↓ cAMP
    H3(301)NDNF
    H3(373)Hippocampus, substantia nigra, amygdala, hypothalamus↓ cAMP
    H3(309)NDNF
    H3(221)NDND
    H3(409)NDND
    H3(329b)NDND
    H3(395)NDND
    H3(379)NDND
    H3(293)NDND
    H3(290)NDND
    H3(351)NDND
    H3(340)NDND
    MonkeyH3(445)Frontal cortex, parietal cortex, occipital cortex, parahippocampal gyrus, hippocampus, caudate nucleus, putamen, amygdala, thalamus, cerebellum↑ [Ca2+]iYao et al., 2003; Strakhova et al., 2008
    H3(413)Frontal cortex, parietal cortex, para-hippocampal gyrus, caudate nucleus, putamen, amygdala, thalamus↑ [Ca2+]i
    H3(410)Frontal cortex, parietal cortex, parahippocampal gyrus, caudate nucleus, putamen, amygdala, thalamus↑ [Ca2+]i
    H3(335)Frontal cortex, parietal cortex, occipital cortex, parahippocampal gyrus, Hippocampus, caudate nucleus, putamen, amygdala, thalamus, cerebellumNF
    RatH3(445)Cerebral cortex, hippocampus, midbrain, hypothalamus, striatum, brainstem, cerebellum, olfactory tuberculum, spinal cord↓ cAMP,Lovenberg et al., 2000; Drutel et al., 2001; Morisset et al., 2001; Bakker et al., 2006; Gbahou et al., 2012
    ↑ p42/p44-MAPK
    H3(413)Cerebral cortex, hippocampus, midbrain, striatum↓ cAMP,
    ↑ p42/p44-MAPK
    ↑ [3H]AA release
    ↑ [35S]-GTPγS binding
    H3(410)Cerebral cortex, hippocampus, midbrain, striatumND
    H3(397)Cerebral cortex, hippocampus, midbrain, hypothalamus, striatum, olfactory tuberculum↓ cAMP,
    ↑ p42/p44-MAPK
    H3(497)Cortex layers II–VIb, caudate-putamen, piriform cortex, hippocampusNF
    H3(465)Cortex layers II–VIb, caudate-putamen, piriform cortex, hippocampusNF
    H3(449)Cortex layers II–VIb, caudate-putamen, piriform cortex, hippocampusNF
    MouseH3(445)Cerebral cortex, striatum, hypothalamus↑ [Ca2+]iChen et al., 2003; Rouleau et al., 2002
    H3(413)Cerebral cortex, striatum, hypothalamusND
    H3(397)Cerebral cortex, striatum, hypothalamusND
    Guinea pigH3(445)Cerebral cortex, striatumNDTardivel-Lacombe et al., 2000
    H3(415)Cerebral cortex, striatumND
    DogH3(ND)NDNDIreland-Denny et al., 2001
    • ↑, increase; ↓, decrease; AA, arachidonic acid; [Ca2+]i, intracellular Ca2+ concentration; ND, not determined; NF, nonfunctional.

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    TABLE 2

    Affinities of the H3R for agonists and antagonists

    Data reported as Ki were converted to pKi. For recombinant receptors all values refer to the H3R of 445 aa.

    pKi
    RatMouseGuinea PigMonkeyDogHuman
    Imidazole-Containing Agonists
     HistamineNative
    8.27a7.92 ± 0.54 (high)b7.58a7.88c8.50 ± 0.08d8.59 ± 0.08d
    8.28e6.09 ± 0.61 (low)b8.18 ± 0.15d8.63f
    7.92g8.08c
    8.29 ± 0.03d
    8.20 ± 0.10e
    8.30f
    8.13i
    7.82j
    Recombinant
    7.87g8.78 ± 0.10k7.81g
    8.57f8.58f
    7.69l7.88l
    5.70 ± 0.15m8.20 ± 0.04n
    7.89 ± 0.07n8.55 ± 0.01k
    8.00 ± 0.10o
    8.03 ± 0.06p
    8.30 ± 0.10q
    8.60 ± 0.00r
    8.50s
    8.40 ± 0.20t
     RAMHNative
    8.88a,e7.91 ± 0.09 (high)b8.49a8.50c8.93 ± 0.19d9.15 ± 0.06d
    8.82g6.67 ± 0.21 (low)b8.63 ± 0.25d8.82c
    8.71 ± 0.08d9.48 ± 0.16u9.16 ± 0.07v
    8.95i10.07 ± 0.16u
    8.71 ± 0.08v
    Recombinant
    8.72g8.40j9.55 ± 0.04k8.67g
    8.44l8.56l
    6.40 ± 0.20m8.91 ± 0.07n
    8.62 ± 0.07n9.41 ± 0.05k
    9.35 ± 0.20v8.20 ± 0.10o
    8.36 ± 0.07p
    8.92 ± 0.11q
    9.00 ± 0.10r
    9.16 ± 0.08v
    8.56w
     SAMHNative
    7.30a5.93 ± 0.04b7.30a7.69c7.79 ± 0.11d7.49c
    7.33 ± 0.06d7.63 ± 0.18d8.33 ± 0.18d
    7.11i
    Recombinant7.20 ± 0.10o
    7.60 ± 0.20r
     NAMHNative
    8.92g8.67 ± 0.27d8.76c9.15 ± 0.09d9.41 ± 0.06d
    8.78 ± 0.13d9.99 ± 0.24u9.08c
    9.15i10.31 ± 0.24u
    Recombinant8.61g
    8.82g9.22 ± 0.03n
    8.70 ± 0.09n8.95j8.40 ± 0.10o
    9.00 ± 0.10r
    9.80s
     ImmepipNative
    9.30g9.50 ± 0.66 (high)b8.68 ± 0.34d9.25 ± 0.06d9.58 ± 0.06d
    8.99 ± 0.20d7.48 ± 0.33 (low)b
    Recombinant
    8.85g9.79j8.79g
    7.50 ± 0.08m9.30 ± 0.10o
    9.32 ± 0.04p
    9.51 ± 0.03q
    9.40 ± 0.10r
    9.70s
    9.40 ± 0.10t
    9.30x
     ImetitNative
    10.00e9.09 ± 0.18 (high)b8.99 ± 0.25d9.01c9.31 ± 0.06d9.67 ± 0.06d
    10.00g7.02 ± 0.60 (low)b9.50c
    9.46 ± 0.10d9.79 ± 0.07v
    9.82i
    9.53 ± 0.09v
    Recombinant9.69j
    9.69g9.84 ± 0.03k9.22g
    9.38 ± 0.08n9.20 ± 0.05n
    10.11 ± 0.10v9.59 ± 0.09k
    8.80 ± 0.10o
    9.23 ± 0.19q
    9.40 ± 0.10r
    9.70s
    9.59 ± 0.09v
     ImpentamineRecombinant
    6.90 ± 0.06m8.84 ± 0.06n
    10.11 ± 0.05n8.30 ± 0.10o
    8.29 ± 0.14p
    8.50 ± 0.10r
     ProxyfanNative
    8.51 ± 0.05v8.32 ± 0.13u8.38 ± 0.13v
    8.80 ± 0.23u
    Recombinant
    8.53l8.56l
    8.08 ± 0.10n7.90 ± 0.10o
    8.62 ± 0.10v8.35 ± 0.06v
    8.40 ± 0.20r
    7.87 ± 0.07n
     VUF 5296Native
    7.60 ± 0.10h
    Recombinant
    7.17 ± 0.09p
     VUF 5297Native
    8.76 ± 0.10e
    Recombinant
    8.03 ± 0.08p
     MethimepipRecombinant
    9.00 ± 0.10o
    9.00 ± 0.10x
    Imidazole-Containing AntagonistspKi
     ThioperamideNative
    8.67a8.37 ± 0.12b8.69a6.61c8.17 ± 0.15d7.13 ± 0.06d
    7.99g8.30 ± 0.15y8.34 ± 0.12d7.91 ± 0.10y7.21f
    8.10 ± 0.06d8.69 ± 0.05u8.17 ± 0.12aa6.69c
    8.12f9.08 ± 0.13u7.18 ± 0.01aa
    8.39i8.34 ± 0.11aa
    8.85z
    8.48 ± 0.01y
    8.15 ± 0.06aa
    Recombinant
    8.37g8.49 ± 0.05y7.19 ± 0.03k7.23g
    8.49f7.13f
    8.18l7.22l
    7.20 ± 0.08m7.34 ± 0.04n
    7.94 ± 0.04n7.24 ± 0.06k
    8.62 ± 0.06y7.30 ± 0.10o
    8.44 ± 0.07aa7.34 ± 0.13q
    8.40 ± 0.20bb7.70 ± 0.20r
    8.44 ± 0.07cc7.70s
    6.90 ± 0.10t
    7.85w
    7.12 ± 0.10y
    7.14 ± 0.06aa
    7.40 ± 0.33bb
    7.14 ± 0.06cc
     CiproxifanNative
    9.15 ± 0.05d9.10 ± 0.16y8.70 ± 0.08d8.20 ± 0.08d6.99 ± 0.08d
    9.18f8.76 ± 0.07dd7.46 ± 0.10y7.04f
    9.22 ± 0.05v8.24 ± 0.06dd7.05 ± 0.07v
    8.91 ± 0.04y6.72 ± 0.14y
    9.20 ± 0.04dd7.05 ± 0.06dd
    Recombinant
    9.36f9.08 ± 0.08y7.18 ± 0.05k7.20f
    8.40l7.33l
    8.87 ± 0.08n7.03 ± 0.12n
    9.38 ± 0.07v7.20 ± 0.04k
    9.29 ± 0.05y7.17 ± 0.04q
    9.29 ± 0.09cc7.40 ± 0.10r
    9.29 ± 0.09dd7.20 ± 0.04v
    7.02w
    6.96 ± 0.06y
    7.20 ± 0.05cc
    7.20 ± 0.05dd
     IodoproxyfanNative
    9.69i8.86 ± 0.16b9.76 ± 0.23u
    10.00 ± 0.09u
    Recombinant
    9.20 ± 0.10o
     ClobenpropitNative
    9.30g9.28 ± 0.16b9.65 ± 0.22d8.65c10.09 ± 0.13d9.08 ± 0.13d
    9.38 ± 0.08d9.57 ± 0.09y9.65 ± 0.20aa9.84 ± 0.12y8.24c
    9.31i10.09 ± 0.11aa9.11 ± 0.11v
    9.45 ± 0.08v9.11 ± 0.11y
    9.53 ± 0.11y9.11 ± 0.12aa
    9.45 ± 0.08aa
    Recombinant
    9.39g9.50j9.72 ± 0.10k9.22g
    8.85l9.70 ± 0.08y8.61l
    8.30 ± 0.02m9.34 ± 0.06n
    9.11 ± 0.06n9.43 ± 0.03k
    9.82 ± 0.07v8.60 ± 0.10o
    9.59 ± 0.09y8.79 ± 0.08q
    9.75 ± 0.01aa9.30 ± 0.20r
    9.30s
    9.47 ± 0.04v
    9.23w
    9.47 ± 0.19y
    9.44 ± 0.04aa
     IodophenpropitNative
    9.23 ± 0.10d9.24 ± 0.21b9.39 ± 0.21d9.59 ± 0.09d8.45 ± 0.14d
    10.08 ± 0.11u
    9.96 ± 0.23u
    Recombinant8.20 ± 0.10o
    9.10 ± 0.20r
     SCH 79687Native
    8.72ee7.88ee
     VUF 5681Recombinant
    8.35 ± 0.11p
    8.90 ± 0.30r
     BurimamideNative
    8.18 ± 0.15d6.28 ± 0.2b8.27 ± 0.05d8.42 ± 0.13d8.34 ± 0.21d
    7.16i
    Recombinant
    7.90 ± 0.10o
    Non-imidazole antagonistspKi
     JNJ-5207852Recombinant
    8.90 ± 0.17bb9.24 ± 0.21bb
     ABT-239Native
    7.92 ± 0.11y7.96 ± 0.08y8.59 ± 0.12ff8.61 ± 0.20y8.34 ± 0.06ff
    8.49 ± 0.04ff8.41 ± 0.07ff
    Recombinant
    8.52 ± 0.08y8.42 ± 0.07y9.51 ± 0.10y
    8.87 ± 0.04cc9.35 ± 0.04cc
    8.91 ± 0.04ff9.35 ± 0.04ff
     NNC 38-1049Recombinant
    8.29gg8.92w
     A-331440Native
    7.66f7.64f
    7.73 ± 0.08hh7.63 ± 0.05hh
    Recombinant
    8.20f8.71 ± 0.06k8.48f
    8.23 ± 0.04hh8.45 ± 0.05k
    7.75 ± 0.04q
    8.00r
    8.45 ± 0.05hh
     A-349821Native
    9.12 ± 0.14hh9.37 ± 0.08hh
    Recombinant
    8.78 ± 0.12cc9.67 ± 0.14k9.55 ± 0.09k
    8.78 ± 0.12hh9.20 ± 0.10r
    9.39 ± 0.08cc
    9.39 ± 0.08hh
     UCL1972Native
    7.41ii
     GSK189254Native
    8.51 ± 0.11y8.89 ± 0.13y8.83 ± 0.09y9.59 ± 0.15y
    Recombinant
    9.17 ± 0.09y8.76 ± 0.06y9.90 ± 0.18y
     PitolisantNative
    7.85jj
    Recombinant
    8.56jj
    • SAMH, S-α-methylhistamine.

    • ↵a Arrang et al., 1987a.

    • ↵e Garbarg et al., 1992.

    • ↵g Lovenberg et al., 2000.

    • ↵d Ireland-Denny et al., 2001.

    • e De Esch et al., 1999.

    • ↵f Hancock et al., 2004a.

    • ↵i Ligneau et al., 1994.

    • ↵l Ligneau et al., 2000.

    • ↵m Drutel et al., 2001.

    • ↵n Schnell et al., 2010.

    • ↵b Jansen et al., 2000.

    • ↵j Chen et al., 2003.

    • ↵c West et al., 1999.

    • ↵k Strakhova et al., 2008.

    • ↵o Lim et al., 2005.

    • ↵p Kitbunnadaj et al., 2003.

    • ↵q Flores-Clemente et al., 2013.

    • ↵r Bongers et al., 2007b.

    • ↵s Lovenberg et al., 1999.

    • ↵t Bongers et al., 2007c.

    • ↵v Krueger et al., 2005.

    • ↵u Harper et al., 1999.

    • ↵w Zaragoza et al., 2004.

    • ↵x Kitbunnadaj et al., 2005.

    • ↵z Sánchez-Lemus and Arias-Montaño, 2004.

    • ↵y Medhurst et al., 2007.

    • ↵aa Esbenshade et al., 2003.

    • ↵bb Barbier et al., 2004.

    • ↵cc Cowart et al., 2005.

    • ↵dd Esbenshade et al., 2004.

    • ↵ee McLeod et al., 2003.

    • ↵ff Esbenshade et al., 2005.

    • ↵gg Malmlöf et al., 2005.

    • ↵hh Hancock et al., 2004b.

    • ↵ii Ganellin et al., 1998.

    • View popup
    TABLE 3

    Potencies of H3R agonists and antagonists

    For recombinant receptors all values refer to the full-length (445 aa) receptor.

    DrugpIC50 or pEC50pA2pKBpD2
    cAMPCa2+MAPKGTPγSPI3K/ Akt
    RAMH8.50 ± 0.10 (r)a8.44 ± 0.11b7.94 ± 0.17 (h)c8.50 ± 0.14 (h)c7.60 ± 0.05d
    9.50 ± 0.10e7.92f8.00 ± 0.10g8.50 ± 0.10a
    9.17 ± 0.03h8.22f7.65 (r)f
    8.22 ± 0.35 (h)c8.50 ± 0.13i8.02, 8.42 (h)f
    8.20 ± 0.10g
    8.67 (r)f
    8.01 (h)f
    9.47 ± 0.18i
    9.54 ± 0.06j
    SAMH8.00 ± 0.10e6.60 ± 0.10g6.21 ± 0.15d
    6.80 ± 0.10g
    8.31 ± 0.01j
    Histamine8.30 ± 0.10e7.66, 7.81, 7.75, 7.76k7.30 ± 0.10g6.46 ± 0.18d
    8.01 ± 0.03h7.99 ± 0.09b7.40 ± 0.10l
    7.40 ± 0.20g7.82 ± 0.09i
    8.63 ± 0.10i
    8.55 ± 0.05j
    Imetit9.90 ± 0.10e8.13, 8.03, 8.40, 8.48k8.60 ± 0.10g7.80 ± 0.10d
    9.66 (r)f8.47 ± 0.08b8.69 (r)f
    8.39 (h)f8.14f8.53, 8.71 (h)f
    8.92 ± 0.04m8.04f
    9.79 ± 0.20i8.86 ± 0.20i
    9.91 ± 0.05j
    Immepip9.40 ± 0.10 (r)a8.80 ± 0.10g9.40n8.35 ± 0.08d
    10.40 ± 0.10e9.40 ± 0.10a
    9.88 ± 0.02h
    9.00 ± 0.10g
    9.90 ± 0.10n
    9.90 ± 0.0o
    7.88q
    10.30 ± 0.14j
    Impentamine8.1 (r)a7.50 ± 0.10q
    8.40 ± 0.10e8.10 ± 0.10a
    8.63 ± 0.08h
    9.17 ± 0.11i
    8.43 ± 0.08j
    NAMH9.40 ± 0.10e8.03, 8.15, 8.34, 8.22k7.90 ± 0.10g7.17 ± 0.07d
    8.50 ± 0.10g
    9.45 ± 0.05j
    Methimepip9.50 ± 0.20e
    9.50 ± 0.20o
    VUF 52967.24 ± 0.04h6.15 ± 0.08l
    VUF 52978.23 ± 0.14h6.64 ± 0.06l
    Proxyfan8.50 ± 0.10e7.43 ± 0.06b7.50 ± 0.10g
    7.83(r)f7.61, 7.11f7.33 (r)f
    6.86 (h)f6.20, 5.89f7.49, 7.68 (h)f
    7.73f
    7.61f
    8.31 ± 0.11j
    Thioperamide7.50 ± 0.10e8.06 ± 0.10 (r)q7.00n8.44 ± 0.45d6.90 ± 0.10t
    7.60 ± 0.20g7.41 ± 0.11 (h)q8.44 ± 0.49 (gp)r8.13 ± 0.14 (r)q
    7.10 ± 0.20n6.90 ± 0.10g7.39 ± 0.04 (h)q
    7.88p7.49 ± 0.34s9.11 ± 0.14 (r)q
    7.41 ± 0.12 (h)t6.82 ± 0.05 (h)q
    8.06 ± 0.10 (r)t7.09 ± 0.08 (mk)b
    6.82 ± 0.06 (h)t
    6.10 ± 0.12 (h)t
    7.39 ± 0.04 (h)t
    6.82 ± 0.06 (h)t
    7.61 ± 0.14 (r)t
    8.13 ± 0.14 (r)t
    8.95v
    Ciproxifan5.39, 5.30f6.57, 6.58f8.87 ± 0.16 (r)q8.12 ± 0.56d8.78 ± 0.12 (r)q
    7.04 ± 0.17 (h)q8.12 ± 0.56s7.03 ± 0.13 (h)q
    7.16 ± 0.19s9.42 ± 0.11 (r)q
    7.04 ± 0.17 (h)s6.86 ± 0.07 (h)q
    8.87 ± 0.16 (r)s7.23 ± 0.04 (mk)b
    9.10 (r)f
    6.59 (h)f
    6.84 ± 0.08t
    6.59 ± 0.04 (h)s
    7.07 ± 0.13 (h)s
    6.84 ± 0.08 (h)s
    9.20 ± 0.10 (r)s
    8.78 ± 0.12 (r)s
    Burimamide7.00 ± 0.10e8.05 ± 0.68d7.56v
    6.65 ± 0.10j
    Iodophenpropit8.50 ± 0.10e9.14 ± 0.61d
    8.50 ± 0.40g
    Iodoproxyfan10.30 ± 0.10e
    Clobenpropit9.40 ± 0.10e7.41, 7.10f8.07 ± 0.66t9.66 ± 0.49d9.80 ± 0.03 (mk)b
    6.79, 6.55f9.66 ± 0.49t9.03 (r)f
    8.35 (h)f
    8.21 ± 0.10 (h)t
    9.04 ± 0.11 (r)t
    8.91 ± 0.06 (h)t
    VUF 56818.41 ± 0.10j8.08 ± 0.03h
    A-3314407.07 ± 0.24 (r)q7.70n7.60 ± 0.12 (r)q
    7.70 ± 0.08 (h)q8.16 ± 0.04 (h)q
    7.38 ± 0.10 (r)q
    7.60 ± 0.10g7.37 ± 0.29 (h)q
    7.81 ± 0.02 (mk)b
    A-3498219.00 ± 0.40g9.20 ± 0.10g9.47 ± 0.56s9.67 ± 0.05 (mk)b
    9.09 ± 0.08 (h)s8.27 ± 0.12u
    8.57 ± 0.09 (r)s8.24 ± 0.10 (h)s
    9.26 ± 0.02 (h)s
    8.27 ± 0.12r (h)s
    8.08 ± 0.10 (r)s
    8.62 ± 0.11 (r)s
    ABT-2297.87 ± 0.15 (r)u
    7.89 ± 0.04 (h)w
    9.04 ± 0.04 (h)w
    7.87 ± 0.15 (h)w
    7.60 ± 0.05 (r)w
    8.34 ± 0.14 (r)w
    8.74 ± 0.44 (gp)w
    GSK1892548.20 ± 0.12m9.06 ± 0.02m
    JNJ-52078528.94 (r)x
    9.84 (h)x
    NCC 38-10498.63y
    Pitolisant9.79z
    • Gp, guinea pig; h, human; mk, monkey; NAMH, Nα-methylhistamine; r, rat.

    • ↵a Drutel et al., 2001.

    • ↵b Strakhova et al., 2008.

    • ↵c Flores-Clemente et al., 2013.

    • ↵d Ireland-Denny et al., 2001.

    • ↵e Lim et al., 2005.

    • ↵f Krueger et al., 2005.

    • ↵g Bongers et al., 2007b.

    • ↵h Kitbunnadaj et al., 2003.

    • ↵i Uveges et al., 2002.

    • ↵j Baker, 2008.

    • ↵k Chen et al., 2003.

    • ↵l De Esch et al., 1999.

    • ↵m Medhurst et al., 2007.

    • ↵n Bongers et al., 2007c.

    • ↵o Kitbunnadaj et al., 2005.

    • ↵p Sánchez-Lemus and Arias-Montaño, 2004.

    • ↵q Hancock et al., 2004a.

    • ↵r Lovenberg et al., 2000.

    • ↵s Esbenshade et al., 2004.

    • ↵t Esbenshade et al., 2003.

    • ↵u Cowart et al., 2005.

    • ↵v Hew et al., 1990.

    • ↵w Esbenshade et al., 2005.

    • ↵x Barbier et al., 2004.

    • ↵y Malmlöf et al., 2005.

    • ↵z Ligneau et al., 2007.

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Molecular Pharmacology: 90 (5)
Molecular Pharmacology
Vol. 90, Issue 5
1 Nov 2016
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Research ArticleMinireview—A Latin American Perspective On G Protein-Coupled Receptors

Histamine H3 Receptor

Gustavo Nieto-Alamilla, Ricardo Márquez-Gómez, Ana-Maricela García-Gálvez, Guadalupe-Elide Morales-Figueroa and José-Antonio Arias-Montaño
Molecular Pharmacology November 1, 2016, 90 (5) 649-673; DOI: https://doi.org/10.1124/mol.116.104752

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Research ArticleMinireview—A Latin American Perspective On G Protein-Coupled Receptors

Histamine H3 Receptor

Gustavo Nieto-Alamilla, Ricardo Márquez-Gómez, Ana-Maricela García-Gálvez, Guadalupe-Elide Morales-Figueroa and José-Antonio Arias-Montaño
Molecular Pharmacology November 1, 2016, 90 (5) 649-673; DOI: https://doi.org/10.1124/mol.116.104752
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    • The Brain Histaminergic System
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