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Can cloned receptors aid drug research?

Published online by Cambridge University Press:  05 December 2011

Paul R. Hartig
Paul R. Hartig
Affiliation:
Synaptic Pharmaceuticals, 215 College Road, Paramus, N.J. 07652, U.S.A.
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Synopsis:

Over 50 different neurotransmitter and hormone receptors have been cloned, transfected and characterised. Within the pharmaceutical industry, the thrust of this research is now moving from receptor cloning to focussed application of these new tools to the task of drug development. With human receptor clones now available, it is possible to target drug design to single human proteins from the inception of a drug-design project. A critical question is whether human genes will express a human pharmacology when expressed in non-human, non-neuronal cell lines. Relevant results from studies with the human serotonin 5-HT2 and 5-HT1D receptors are presented, including the cloning of a rat 5-HT1B receptor which is homologous to a human 5-HT1D receptor gene. Another issue is the relationship between agonist and antagonist binding sites. The ability to study individual human receptors in selected cell lines which are free from interfering receptors has helped to advance our understanding of this relationship. Studies comparing agonist and antagonist binding sites of the human 5-HT2 receptor are described. Finally, the fact that so many neurotransmitter receptors belong to the same gene superfamily, the G-protein-coupled or 7TM (7 transmembrane domain) receptor superfamily, allows us to form new insights about receptor structure and function. Examples where comparative studies of gene sequences are helping to predict pharmacological properties of drugs are described.

Type
Research Article
Information
Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences , Volume 99 , Issue 1-2: The Advancement of Drug Discovery , 1992 , pp. 19 - 25
Copyright
Copyright © Royal Society of Edinburgh 1992

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References

Adham, N., Romanienko, P., Hartig, P., Weinshank, R. L., & Branchek, T., (1992). The rat 5-hydroxy-tryptamine1B receptor is the species homolog of the human 5-hydroxytryptamine1Dβ receptor. Molecular Pharmacology 41, 1–7.Google Scholar
Branchek, T., Adham, N., Macchi, M., Kao, H.-T. & Hartig, P. R. 1990. [3H]-DOB (4-bromo-2, 5-dimethoxyphenylisopropylamine) and [3H]-ketanserin label two affinity states of the cloned human 5-HT2 receptor. Molecular Pharmacology 38, 681–8.Google Scholar
Branchek, T., Zgombick, J., Macchi, M., Hartig, P., & Weinshank, R. 1991. Cloning and expression of a human 5-HT1D receptor. In Serotonin: molecular biology, receptors, and functional effects, pp. 21–32, eds Saxena, P., & Fozard, J. R., Basel: Birkhauser.CrossRefGoogle Scholar
Chapot, M., Eshdat, Y., Marullo, S., Guillet, J., Charbit, A., Strosberg, A., & Delavier-Klutchko, C. 1990. Localization and characterization of three different beta-adrenergic receptors expressed in Escherichia coli. European Journal of Biochemistry 187, 137–44.CrossRefGoogle ScholarPubMed
Freissmuth, M., Casey, P., & Gilman, A. 1989. G proteins control diverse pathways of transmembrane signaling. FASEB Journal 3, 2125–31.CrossRefGoogle ScholarPubMed
Hartig, P., Kao, H.-T., Macchi, M., Adham, N., Zgombick, J., Weinshank, R., & Brancheck, T. 1990. The molecular biology of serotonin receptors: an overview. Neuropsychopharmacology 3, 335–47.Google ScholarPubMed
Hartig, P., Adham, N., Zgombick, J., Weinshank, R., & Branchek, T. 1992. Molecular biology of the 5-HT1 receptor subfamily. Drug Development Research (in press).CrossRefGoogle Scholar
Hoyer, D., Pazos, A., Probst, A., & Palacios, J. M. 1986. Serotonin receptors in the human brain. II. Characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites. Brain Research 376, 97–107.CrossRefGoogle ScholarPubMed
Hoyer, D., & Middlemiss, D. N. 1989. The pharmacology of the terminal 5-HT autoreceptors in mammalian brain: Evidence for species differences. Trends in Pharmacological Science 10, 130–32.CrossRefGoogle Scholar
Kobilka, B., Matsui, H., Kobilka, T., Yang-Feng, T., Francke, U., Caron, M., Leflcowitz, R., & Regan, J. 1987. Cloning, sequencing, and expression of the gene coding for the human platelet α2-adrenergic receptor. Science 238, 650–56.CrossRefGoogle Scholar
Lyon, R. A., Davis, K. H., & Titeler, M. 1987. [3H]DOB (4-bromo-2, 5-dimethoxyphenylisopropylamine) labels guanyl nucleotide-sensitive state of cortical 5-HT2 receptors. Molecular Pharmacology 31, 194–9.Google ScholarPubMed
Pazos, A., Hoyer, D., & Palacios, J. 1984. Mesulergine, a selective serotonin-2 ligand in the rat cortex, does not label these receptors in porcine and human cortex: evidence for species differences in brain serotonin-2 receptors. European Journal of Pharmacology 106, 531–8.CrossRefGoogle Scholar
Pierce, P., & Peroutka, S. J. 1989. Evidence for distinct 5-Hydroxytryptamine receptor binding site subtypes in cortical membrane preparations. Journal of Neurochemistry 52, 656–8.CrossRefGoogle ScholarPubMed
Teitler, M., Leonhardt, S., Weisberg, E., & Hoffman, B. 1990. 4-[125I]Iodo-(2,5-dimethoxy)phenylisopropylamine and [3H]ketanserin labeling of 5-HT2 receptors in mammalian cells transfected with a rat 5-HT2 cDNA: evidence for multiple states and not multiple 5-HT2 receptor subtypes. Molecular Pharmacology 38, 594–8.Google Scholar