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OtherNEUROPHARMACOLOGY

The Pharmacological Characterization of a Novel Selective 5-Hydroxytryptamine1A Receptor Antagonist, NAD-299

Lars Johansson, Daniel Sohn, Seth-Olof Thorberg, David M. Jackson, Diana Kelder, Lars-Gunnar Larsson, Lucy Rényi, Svante B. Ross, Carin Wallsten, Håkan Eriksson, Ping-Sheng Hu, Eva Jerning, Nina Mohell and Anita Westlind-Danielsson
Journal of Pharmacology and Experimental Therapeutics October 1997, 283 (1) 216-225;
Lars Johansson
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Daniel Sohn
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Seth-Olof Thorberg
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David M. Jackson
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Diana Kelder
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Lars-Gunnar Larsson
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Lucy Rényi
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Svante B. Ross
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Carin Wallsten
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Håkan Eriksson
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Ping-Sheng Hu
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Eva Jerning
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Nina Mohell
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Anita Westlind-Danielsson
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Abstract

The pharmacological properties of a novel selective 5-hydroxytryptamine1A (5-HT1A) receptor antagonist, NAD-299 [(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate] were examined in vitro and in vivo and compared with the reference 5-HT1A receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazin-yl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride]. The new compound had high affinity for 5-HT1A receptors in vitro with a Ki value of 0.6 nM. The only other receptors for which NAD-299 had affinity less than 1 μM werealpha-1 and beta adrenoceptors withKi values of 260 and 340 nM, respectively. Thus, the selectivity of NAD-299 for 5-HT1A receptors was more than 400 times. WAY-100635 had considerably higher affinity than NAD-299 for alpha-1 adrenoceptors (Ki = 45 nM) and dopamine D2 and D3 receptors (Ki = 79 and 67 nM, respectively). Like WAY-100635, NAD-299 competitively blocked 5-HT-induced inhibition of vasoactive intestinal peptide-stimulated cAMP production in GH4ZD10 cells and had no intrinsic activity. Both compounds were therefore 5-HT1A receptor antagonists in vitro and also behaved as such inin vivo experiments. Thus, they competitively antagonized the 8-hydroxy-2-(di-n-propylamino)tetralin-induced 5-HT behavioral effects, hypothermia, corticosterone secretion and inhibition of passive avoidance behavior without causing any actions of their own. The effective dose of NAD-299 varied between 0.03 and 0.35 μmol/kg s.c., depending on the test and the dose of 8-hydroxy-2-(di-n-propylamino)tetralin.

Footnotes

  • Send reprint requests to: Dr Svante B. Ross, Behavioural and Biochemical Pharmacology, Preclinical R & D, Astra Arcus AB, S-151 85 Södertälje, Sweden.

  • Abbreviations:
    DA
    dopamine
    DOPA
    l-3,4-dihydroxyphenylalanine
    8-OH-DPAT
    8-hydroxy-2-(di-n-propylamino)tetralin
    5-HT
    5-hydroxytryptamine
    IBMX
    3-isobutyl-1-methylxanthine
    5-HTP
    5-hydroxytryptophan
    NAD-299
    (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate
    NSD 1015
    3-hydroxybenzylhydrazine dihydrochloride
    (S)-UH-301
    (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin
    VIP
    vasoactive intestinal peptide
    WAY-100135
    N-tert-butyl-3-(4-(2-methoxyphenyl)piperacine-1-yl)-2-phenylpropanamide dihydrochloride
    WAY-100635
    N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride
    CHO
    Chinese hamster ovary
    FCS
    fetal calf serum
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    EDTA
    ethylenediaminetetraacetic acid
    ANOVA
    analysis of variance
    AMPA
    dl-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
    DHA
    dihydroalprenolol
    GABA
    γ-aminobutyric acid
    NMDA
    N-methyl-d-aspartate
    TBPS
    tert-butylbicyclophosphothionate
    QNB
    l-quinuclidinyl benzilate
    • Received December 31, 1996.
    • Accepted June 9, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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OtherNEUROPHARMACOLOGY

The Pharmacological Characterization of a Novel Selective 5-Hydroxytryptamine1A Receptor Antagonist, NAD-299

Lars Johansson, Daniel Sohn, Seth-Olof Thorberg, David M. Jackson, Diana Kelder, Lars-Gunnar Larsson, Lucy Rényi, Svante B. Ross, Carin Wallsten, Håkan Eriksson, Ping-Sheng Hu, Eva Jerning, Nina Mohell and Anita Westlind-Danielsson
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 216-225;

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OtherNEUROPHARMACOLOGY

The Pharmacological Characterization of a Novel Selective 5-Hydroxytryptamine1A Receptor Antagonist, NAD-299

Lars Johansson, Daniel Sohn, Seth-Olof Thorberg, David M. Jackson, Diana Kelder, Lars-Gunnar Larsson, Lucy Rényi, Svante B. Ross, Carin Wallsten, Håkan Eriksson, Ping-Sheng Hu, Eva Jerning, Nina Mohell and Anita Westlind-Danielsson
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 216-225;
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