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OtherNEUROPHARMACOLOGY

In Vitro and In Vivo Characterization of the Dopamine D4 Receptor, Serotonin 5-HT2AReceptor and Alpha-1 Adrenoceptor Antagonist (R)-(+)-2-Amino-4-(4-Fluorophenyl)- 5-[1-[4-(4-Fluorophenyl)-4-Oxobutyl]Pyrrolidin-3-yl]Thiazole (NRA0045)

Shigeru Okuyama, Shigeyuki Chaki, Ryoko Yoshikawa, Yoshiko Suzuki, Shin-Ichi Ogawa, Yasuko Imagawa, Naoya Kawashima, Yoko Ikeda, Toshihito Kumagai, Atsuro Nakazato, Masashi Nagamine and Kazuyuki Tomisawa
Journal of Pharmacology and Experimental Therapeutics July 1997, 282 (1) 56-63;
Shigeru Okuyama
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Shigeyuki Chaki
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Ryoko Yoshikawa
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Yoshiko Suzuki
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Shin-Ichi Ogawa
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Yasuko Imagawa
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Naoya Kawashima
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Yoko Ikeda
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Toshihito Kumagai
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Atsuro Nakazato
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Masashi Nagamine
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Kazuyuki Tomisawa
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Abstract

(R)-(+)-2-Amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]pyrrolidin-3-yl]thiazole (NRA0045), a novel thiazole derivative, has high affinities for the human cloned dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 2.54, 0.55 and 0.54 nM, respectively. NRA0045 is approximately 91-fold more potent at the dopamine D4.2 receptor, compared with human cloned dopamine D2L receptor. NRA0045 also has high affinities for the serotonin (5-HT)2A receptor (Ki = 1.92 nM) and alpha-1 adrenoceptor (Ki = 1.40 nM) but weak affinities (IC50 values are approximately 1 μM) for six other neurotransmitter receptors (adenosine1, 5-HT1A, 5-HT1C, dopamine transporter, α2A and α2A) and negligible affinities (IC50 values are over 10−5 M) for 42 other receptors, including neurotransmitters and hormones, ion channels and second messenger systems. Locomotor hyperactivity induced by methamphetamine (1 mg/kg i.p.) in mice was dose-dependently antagonized by NRA0045 (ED50 = 0.5 mg/kg i.p. and 1.9 mg/kg p.o., respectively). Methamphetamine (10 mg/kg i.p.)-induced stereotyped behavior in mice was dose-dependently antagonized by NRA0045, whereas NRA0045 did not exceed 50% inhibition even at the highest dose given (30 mg/kg i.p.). Catalepsy was dose-dependently and significantly induced by NRA0045 in rats, whereas NRA0045 did not exceed 50% induction even at the highest dose given (30 mg/kg i.p.). Thus NRA0045 blocks behaviors associated with activation of the mesolimbic/mesocortical dopaminergic neurons more selectively than behaviors associated with nigrostriatal dopaminergic neurons. In rats, tryptamine-induced clonic seizure, a 5-HT2 receptor-mediated behavior, was also dose-dependently inhibited by NRA0045 (ED50 = 1.7 mg/kg i.p.). Norepinephrine-induced lethality is regarded as being induced through the alpha-1 adrenoceptor. NRA0045 dose-dependently antagonized norepinephrine-induced lethality in rats (ED50= 0.2 mg/kg i.p.). Thus NRA0045 may have a unique antipsychotic activity with regard to dopamine D4 and 5-HT2Areceptors and alpha-1 adrenoceptor antagonistic activities, without producing the extrapyramidal side effects.

Footnotes

  • Send reprint requests to: Shigeru Okuyama, Ph.D., 1st Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Ohmiya, Saitama 330, Japan.

  • Abbreviations:
    ANOVA
    analysis of variance
    MAP
    methamphetamine
    NRA0045
    (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]pyrrolidin-3-yl]thiazole
    NE
    norepinephrine
    5-HT
    serotonin
    PET
    positron emission tomography
    SPET
    simple PET
    mRNA
    messenger ribonucleic acid
    cDNA
    complementary deoxyribonucleic acid
    RT-PCR
    reverse transcription-polymerase chain reaction
    NMDA
    N-methyl-D-aspartate
    PCP
    phencyclidine
    MK-801
    (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine
    • Received November 11, 1996.
    • Accepted March 6, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 1
1 Jul 1997
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In Vitro and In Vivo Characterization of the Dopamine D4 Receptor, Serotonin 5-HT2AReceptor and Alpha-1 Adrenoceptor Antagonist (R)-(+)-2-Amino-4-(4-Fluorophenyl)- 5-[1-[4-(4-Fluorophenyl)-4-Oxobutyl]Pyrrolidin-3-yl]Thiazole (NRA0045)
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OtherNEUROPHARMACOLOGY

In Vitro and In Vivo Characterization of the Dopamine D4 Receptor, Serotonin 5-HT2AReceptor and Alpha-1 Adrenoceptor Antagonist (R)-(+)-2-Amino-4-(4-Fluorophenyl)- 5-[1-[4-(4-Fluorophenyl)-4-Oxobutyl]Pyrrolidin-3-yl]Thiazole (NRA0045)

Shigeru Okuyama, Shigeyuki Chaki, Ryoko Yoshikawa, Yoshiko Suzuki, Shin-Ichi Ogawa, Yasuko Imagawa, Naoya Kawashima, Yoko Ikeda, Toshihito Kumagai, Atsuro Nakazato, Masashi Nagamine and Kazuyuki Tomisawa
Journal of Pharmacology and Experimental Therapeutics July 1, 1997, 282 (1) 56-63;

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OtherNEUROPHARMACOLOGY

In Vitro and In Vivo Characterization of the Dopamine D4 Receptor, Serotonin 5-HT2AReceptor and Alpha-1 Adrenoceptor Antagonist (R)-(+)-2-Amino-4-(4-Fluorophenyl)- 5-[1-[4-(4-Fluorophenyl)-4-Oxobutyl]Pyrrolidin-3-yl]Thiazole (NRA0045)

Shigeru Okuyama, Shigeyuki Chaki, Ryoko Yoshikawa, Yoshiko Suzuki, Shin-Ichi Ogawa, Yasuko Imagawa, Naoya Kawashima, Yoko Ikeda, Toshihito Kumagai, Atsuro Nakazato, Masashi Nagamine and Kazuyuki Tomisawa
Journal of Pharmacology and Experimental Therapeutics July 1, 1997, 282 (1) 56-63;
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