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Research ArticleNEUROPHARMACOLOGY

The Pharmacological Profile of (R)-3,4-Dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a Selective 5-Hydroxytryptamine1A Receptor Agonist

Lucy Rënyi, John L. Evenden, Christopher J. Fowler, Eva Jerning, Diana Kelder, Desmond Lake-Bakaar, Lars-Gunnar Larsson, Nina Mohell, Maria Sällemark and Svante B. Ross
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 883-893;
Lucy Rënyi
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John L. Evenden
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Christopher J. Fowler
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Eva Jerning
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Diana Kelder
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Desmond Lake-Bakaar
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Lars-Gunnar Larsson
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Nina Mohell
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Maria Sällemark
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Svante B. Ross
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Abstract

The pharmacological properties of the 5-hydroxytryptamine (HT)1A receptor agonist (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide (NAE-086) were examined with in vitro and in vivo techniques. Receptor binding studies demonstrated that NAE-086 was a high-affinity and selective 5-HT1A receptor ligand with aKi value of 4.5 nM in membranes from rat hippocampus. Of 32 other receptors examined NAE-086 had a modest affinity only for the 5-HT7 receptor (Ki = 240 nM). NAE-086 inhibited VIP-stimulated adenylyl cyclase activity in GH4ZD10 cells with 79% of the efficacy of 5-HT. This inhibition was blocked by the 5-HT1A receptor (and β-adrenoceptor) antagonist (−)alprenolol. A minor metabolite of NAE-086 in rats, (R)-3,4-dihydro-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide had a similar receptor profile but had 17 times higher affinity for the 5-HT1A receptor (Ki = 0.26 nM). In vivo, NAE-086 induced all the typical effects of a 5-HT1A receptor agonist in rats: it decreased 5-HT synthesis (5-HTP accumulation) and 5-HT turnover (measured as the ratio of 5-hydroxyindoleacetic acid/5-HT), increased corticosterone secretion, induced the 5-HT1A syndrome (flat body posture and forepaw treading), inhibited the cage-leaving response, and caused hypothermia. All the responses mediated by postsynaptic 5-HT1A receptors were attenuated after single or repeated treatment of the rats with NAE-086. Simultaneously with the development of the tolerance to 5-HT1A receptor-mediated responses, 5-HT2A receptor-mediated responses were enhanced, as judged from the increased number of spontaneous and/or agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-induced wet-dog shake responses. The significance of this behavioral effect in relation to clinical observations is discussed.

Footnotes

  • ↵1 Present address: AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850.

  • ↵2 Present address: Department of Pharmacology, Umeå University, S-901 87 Umeå, Sweden.

  • ↵3 Present address: Acadia Pharmaceuticals, 3911 Sorrento Valley Blvd., San Diego, CA 92121.

  • Abbreviations:
    5-HT
    5-hydroxytryptamine
    ANOVA
    analysis of variance
    CCK
    cholecystokinin
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    DOI
    1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
    DOPA
    l-3,4-dihydroxyphenylalanine
    DPDPE
    [d-Pen2,d-Pen5]-enkephalin
    EEDQ
    1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
    GABA
    γ-aminobutyric acid
    GH4ZD10
    rat pituitary tumor cells
    HPLC
    high-performance liquid chromatography
    5-HIAA
    5-hydroxyindoleacetic acid
    5-HTP
    5-hydroxytryptophan
    8-OH-DPAT
    8-hydroxy-2-(di-n-propylamino)tetralin
    NAE-084
    (S)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide
    NAE-111
    (R)-3,4-dihydro-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide
    NSD 1015
    3-hydroxybenzylhydrazine dihydrochloride
    TBPS
    t-butylbicyclophosphorothionate
    VIP
    vasoactive intestinal polypeptide
    • Received May 16, 2001.
    • Accepted August 29, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Research ArticleNEUROPHARMACOLOGY

The Pharmacological Profile of (R)-3,4-Dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a Selective 5-Hydroxytryptamine1A Receptor Agonist

Lucy Rënyi, John L. Evenden, Christopher J. Fowler, Eva Jerning, Diana Kelder, Desmond Lake-Bakaar, Lars-Gunnar Larsson, Nina Mohell, Maria Sällemark and Svante B. Ross
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 883-893;

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Research ArticleNEUROPHARMACOLOGY

The Pharmacological Profile of (R)-3,4-Dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a Selective 5-Hydroxytryptamine1A Receptor Agonist

Lucy Rënyi, John L. Evenden, Christopher J. Fowler, Eva Jerning, Diana Kelder, Desmond Lake-Bakaar, Lars-Gunnar Larsson, Nina Mohell, Maria Sällemark and Svante B. Ross
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 883-893;
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