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FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia

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Abstract

Rationale

2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213) is a highly selective antagonist at the dopamine D4 receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay.

Objectives

In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry.

Methods

Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study.

Results

A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D4 antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D2 receptor antagonism, but a partial involvement of 5-HT2- and α1-receptors cannot be ruled out at present.

Conclusions

We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.

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Acknowledgements

This work was supported by grants from the ETH Zürich, Switzerland and the Friedrich-Alexander University of Erlangen, Germany. We thank Mr. A.N.A. Ipekian for linguistic revision of the manuscript.

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Authors and Affiliations

  1. Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zürich, Schorenstrasse 16, 8603 , Schwerzenbach, Switzerland

    Frank Boeckler, Holger Russig, Weining Zhang, Boris Ferger & Joram Feldon

  2. Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, 91052 , Erlangen, Germany

    Frank Boeckler, Stefan Löber, Harald Hübner & Peter Gmeiner

  3. Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA

    John Schetz

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  1. Frank Boeckler
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  2. Holger Russig
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  4. Stefan Löber
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Correspondence to Joram Feldon.

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Boeckler, F., Russig, H., Zhang, W. et al. FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia. Psychopharmacology 175, 7–17 (2004). https://doi.org/10.1007/s00213-004-1782-1

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  • DOI: https://doi.org/10.1007/s00213-004-1782-1

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