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Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine

Naturevolume 350, pages610–614 (1991)Cite this article

Abstract

DOPAMINE receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1,D2,D3) have been cloned1–7. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia8,9. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine10 is one of the most favoured antipsychotics because it does not cause tardive dyskinesia11. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water12,13. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.

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Authors and Affiliations

  1. Department of Pharmacology, University of Toronto, Medical Sciences Building, Toronto, Ontario, M5S 1A8, Canada

    Hubert H. M. Van Tol, Hong-Chang Guan, Roger K. Sunahara, Philip Seeman & Hyman B. Niznik

  2. Department of Psychiatry, University of Toronto, Medical Sciences Building, Toronto, Ontario, M5S 1A8, Canada

    Hubert H. M. Van Tol, Philip Seeman & Hyman B. Niznik

  3. Clarke Institute of Psychiatry, Laboratory for Molecular Neurobiology, Toronto, Ontario, M5T 1R8, Canada

    Hubert H. M. Van Tol & Hyman B. Niznik

  4. Vollum Institute for Advanced Biomedical Research, Department of Cell Biology and Anatomy, Oregon Health Sciences University, Portland, Oregon, 97201, USA

    James R. Bunzow & Olivier Civelli

Authors
  1. Hubert H. M. Van Tol

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  2. James R. Bunzow

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  3. Hong-Chang Guan

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  4. Roger K. Sunahara

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  5. Philip Seeman

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  6. Hyman B. Niznik

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  7. Olivier Civelli

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Van Tol, H., Bunzow, J., Guan, HC.et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.Nature350, 610–614 (1991). https://doi.org/10.1038/350610a0

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