Skip to main content
SpringerLink
Log in
Book cover

Drug Discovery and Development pp 97–113Cite as

Use of Intact Tissue Preparations in the Drug Discovery Process

  • Chapter

Abstract

In discussing the usefulness of isolated tissues in the drug discovery process, as with any model utilized in the characterization of a potential new drug, the question of relevance must be ascertained. The biologist usually interprets the effects of a drug on isolated tissues or organs as an action at the receptor level. However, the question does not have to be targeted toward a particular cellular or mechanistic parameter; it can also be more global in nature, e.g., clinical significance in comparison to known active agents. Usually, the more that is known about a chemical entity or clinical disorder, the more relevant are the in vitro tissue screens (see Williams and Malick, this volume).

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Altura, B. M. and Altura, B. T. (1970) Heterogeneity of drug receptors in different segments of rabbit thoracic aorta. Eur. J. Pharmacol. 12, 44–52.

    Article  PubMed  CAS  Google Scholar 

  • Ariens, E. J. and Simonis, A. M. (1962) Drug-receptor interaction. Acta Physiol. Pharmacol. 11, 151–172.

    CAS  Google Scholar 

  • Ariens, E. J. and Simonis, A. M. (1964a) A molecular basis for drug action. J. Pharm. Pharmacol. 16, 137–157.

    Article  CAS  Google Scholar 

  • Ariens, E. J. and Simonis, A. M. (1964b) A molecular basis for drug action. The interaction of one or more drugs with different receptors. J. Phanti. Pharmacol. 16, 289–312.

    Article  CAS  Google Scholar 

  • Ariens, E. J., Van Rossum, J. M., and Koopman, P. C. (1960) Receptor reserve and threshold phenomena. Arch. Int. Pharmacodyn. Ther. 127, 459–478.

    PubMed  CAS  Google Scholar 

  • Ash, A. S. F. and Schild, H. O. (1966) Receptors mediating some actions of histamine. Br. J. Pharmacol. 27, 427–439.

    CAS  Google Scholar 

  • Augstein, J., Farmer, J. B., Lee, T. B., Sheard, P., and Tattersall, M. L. (1973) Selective inhibitor of slow reacting substance of anaphylaxis. Nature (New Biol.) 245, 215–217.

    Article  CAS  Google Scholar 

  • Bach, M. K. (1983) The Leukotrienes: Their Structure, Actions, and Role in Diseases. Current Concepts. Upjohn, Kalamazoo, Michigan.

    Google Scholar 

  • Bach, M. K., Brashler, J. R., and Gorman, R. R. (1977) On the structure of slow reacting substance of anaphylaxis: Evidence of biosynthesis from arachidonic acid. Prostaglandins 14, 21–38.

    Article  PubMed  CAS  Google Scholar 

  • Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R., and Parsons, E. M. (1972) Definition and antagonism of histamine H2 receptors. Nature 236, 385–390.

    Article  PubMed  CAS  Google Scholar 

  • Black, J. W., Duncan, W. A. M., Emmett, J. C., Ganellin, C. R., Hesselbro, T., Parsons, M. E., and Wyllie, J. H. (1973) Metiamide, an orally active histamine H2 receptor antagonist. Agents Action 3, 133–137.

    Article  CAS  Google Scholar 

  • Bohr, D. F. (1973) Vascular smooth muscle updated. Cinc. Res. 32, 665–672.

    CAS  Google Scholar 

  • Bolton, T. B. (1979) Mechanisms of action of transmitters and other substances on smooth muscle. Physiol. Rev. 59, 606–718.

    PubMed  CAS  Google Scholar 

  • Borgeat, P. and Samuelsson, B. (1979a) Transformation of arachidonic acid by rabbit polymorphonuclear leukocytes. Formation of a novel dihydroxyeicosatetraenoic acid. J. Biol. Chem. 254. 2643–2646.

    PubMed  CAS  Google Scholar 

  • Borgeat, P. and Samuelsson, B. (1979b) Metabolism of arachidonic acid in polymorphonuclear leukocytes. Structural analysis of novel hydroxylated compounds. J. Biol. Chem. 254, 7865–7869.

    PubMed  CAS  Google Scholar 

  • Borgeat, P. and Sirois, P. (1981) Leukotrienes: A major step in the understanding of immediate hypersensitivity reactions. J. Med. Chem. 24, 121–126.

    Article  PubMed  CAS  Google Scholar 

  • Brocklehurst, W. E. (1960) The release of histamine and formation of slow reacting substance (SRS-A) during anaphylactic shock. J. Physiol. (Lond.) 151, 416–435.

    CAS  Google Scholar 

  • Cavero, I. and Spedding, M. (1983) “Calcium antagonists:” A class of drugs with a bright future. I. Cellular calcium homeostais and calcium as a coupling messenger. Life Sci. 33, 2571–2581.

    Article  PubMed  CAS  Google Scholar 

  • Chand, N. (1979) FPL-55712-An antagonist of slow reacting substance of anaphylaxis (SRS-A): A review. Agents Actions 9, 133–140.

    Article  PubMed  CAS  Google Scholar 

  • Clark, A. J. (1933) The Mode of Action of Drugs on Cells Arnold, London.

    Google Scholar 

  • Corey, E. J., Clark, D. A., Goto, G., Marfat, A., Mioskowski, C., Samuelsson, B., and Hammarstrom, S. (1980a) Stereospecific total synthesis of a slow reacting substance of anaphylaxis, leukotriene C-1. J. Am. Chem. Soc. 102, 1436–1439.

    Article  CAS  Google Scholar 

  • Corey, E. J., Marfat, A., Goto, G., and Brian, F. (1980b) Leukotriene B: Total synthesis and assignment of stereochemistry. J. Am. Chan. Soc. 102, 7984–7985.

    Article  CAS  Google Scholar 

  • Ehrlich, P. (1913) Chemotherapeutics—scientific principles, methods and results. Lancet 11, 445.

    Google Scholar 

  • Ellrodt, G., Chew, C. Y. C., and Singh, B. N. (1980) Therapeutic implications of slow-channel blockade in cardiocirculatory disorders. Circulation 62, 669–679.

    PubMed  CAS  Google Scholar 

  • Feldberg, W. and Kellaway, C. H. (1938) Liberation of histamine and formation of lysocithin-like substances by cobra venom. J. Physiol. (Lond.) 94, 187–226.

    CAS  Google Scholar 

  • Fleckenstein, A. (1971) Specific Inhibitors and Promoters of Calcium Action in the Excitation-Contraction Coupling of Heart Muscle, in Calcium and the Heart ( Opie, L. and Harris, P., eds.) Academic, London.

    Google Scholar 

  • Fleckenstein, A. (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann. Rev. Pharmacol. Toxicol. 17, 149–166.

    Article  CAS  Google Scholar 

  • Furchgott, R. F. (1955) The pharmacology of vascular smooth muscle. Pharmacol. Rev. 7, 183–265.

    PubMed  CAS  Google Scholar 

  • Furchgott, R. F. (1964) Receptor mechanisms. Ann. Rev. Pharmacol. 4, 21–50.

    Article  CAS  Google Scholar 

  • Furchgott, R. F. (1966) The pharmacologial differentiation of adrenergic receptors. Ann. NY Acad. Sci. 139, 553–570.

    Article  Google Scholar 

  • Furchgott, R. S. (1968) A Critical Appraisal of the Use of Isolated Organ Systems for the Assessment of Drug Action at the Receptor Level, in Importance of Fundamental Principles in Drug Evaluation ( Tedeschi, D. H. and Tedeschi, R. E., eds.) Raven, New York.

    Google Scholar 

  • Gaddum, J. H. (1953) Bioassays and mathematics. Pharmacol. Rev. 5, 87–134.

    PubMed  CAS  Google Scholar 

  • Gillette, J. R. (1968) Problems Associated with the Extrapolation of Data from In Vitro Experiments to Experiments in Intact Animals, in Importance of Fundamental Principles in Drug Evaluation ( Tedeschi, D. H. and Tedeschi, R. E., eds.) Raven, New York.

    Google Scholar 

  • Glossman, H., Ferry, D. R., Lubbecke, F., Mewes, R., and Hofmann, F. (1982) Calcium channels: direct identification with radioligand binding studies. Trends Pharmacol. Sci. 3, 431–437.

    Article  Google Scholar 

  • Hammarstrom, S., Murphy, R. C., Sammuelsson, B., Clark, D. A., Mioskowski, C., and Corey, E. J. (1979) Structure of leukotriene C: Identification of the amino acid part. Biochem. Biophys. Res. Commun. 91, 1266–1272.

    Article  PubMed  CAS  Google Scholar 

  • Janis, R. A. and Scriabine, A. (1983) Sites of action of Ca2+ channel inhibitors. Biochem. Pharmacol. 32, 3499–3507.

    Article  PubMed  CAS  Google Scholar 

  • Janis, R. A., Maurer, S. C., Sarmiento, J. G., Bolger, G. T., and Triggle, D. J. (1982) Binding of [3H] nimodipine to cardiac smooth muscle membrane. Eur. J. Pharmacol. 82, 191–194.

    Article  PubMed  CAS  Google Scholar 

  • Karaki, H. and Weiss, G. B. (1984) Calcium channels in smooth muscle. Gastroenterology 87, 960–970.

    PubMed  CAS  Google Scholar 

  • Kellaway, C. H. and Trethewie, E. R. (1940) Liberation of a slow reacting smooth muscle stimulating substance in anaphylaxis. Q. J. Exp. Physiol. 30, 121–145.

    CAS  Google Scholar 

  • Kenakin, T. P. (1984) The classification of drugs and drug receptors in isolated tissues. Pharmacol. Rev. 36, 165–222.

    PubMed  CAS  Google Scholar 

  • Limbird, L. E. (1986) Cell Surface Receptors: A Short Course On Theory and Methods Nijhoff, Boston.

    Google Scholar 

  • Maxwell, R. A. (1984) The state of the art of the science of drug discovery—an opinion. Drug Dev. Res. 4, 375–389.

    Article  CAS  Google Scholar 

  • Murphy, K. M. M., Gould, R.J., Urgent, B. L., and Snyder, S. H. (1983) A unitary mechanism of calcium antagonist drug action. Proc. Natl. Acad. Sci. USA 80, 860–864.

    Article  PubMed  CAS  Google Scholar 

  • Nickerson, M. (1956) Receptor occupancy and tissue response. Nature (Lond.) 178, 697–698.

    Article  CAS  Google Scholar 

  • Orange, R. P. and Austen, K. F. (1976) The biological assay of slow reacting substances—SRS-A, bradykinin, prostaglandins. Meth. Immunol. Immunochem. 5, 145–149.

    CAS  Google Scholar 

  • Paton, W. D. M. (1961) A theory of drug action based on the rate of drug–receptor combination. Proc. Roy Soc. London B Biol. Sci. 154, 21–69.

    Article  Google Scholar 

  • Piper, P. J. and Samhoun, M. N. (1981) The mechanism of action of leukotrienes C4 and D4 in guinea pig isolated perfused lung and parenchymal strips of guinea pig, rabbit and rat. Prostaglandins 21, 793–803.

    Article  PubMed  CAS  Google Scholar 

  • Prosser, C. L. (1974) Smooth muscle. Ann. Rev. Physiol. 36, 503–535.

    Article  CAS  Google Scholar 

  • Radmark, O., Malmsten, C., Samuelsson, B., Clark, D. A., Goto, G., Marfat, A., and Corey, E. J. (1980) Leukotriene A: Stereochemistry and enzymatic conversion to leukotriene B. Biochem. Biophys. Res. Commun. 92, 954–961.

    Article  PubMed  CAS  Google Scholar 

  • Ruffulo, R. R., Jr. (1982) Review: Important concepts of receptor theory. J. Auton. Pharmacol. 2, 277–295.

    Article  Google Scholar 

  • Samuelsson, B., Borgeat, P., Hammarstrom, S., and Murphy, R. C. (1979) Introduction of a nomenclature: Leukotricnes. Prostaglandins 17, 785–787.

    Article  PubMed  CAS  Google Scholar 

  • Singh, B. N. (1982) Pharmacological basis for the therapeutic applications of slow-channel blocking drugs. Angiology 33, 492–515.

    Article  PubMed  CAS  Google Scholar 

  • Sirois, P., Roy, S., Tetrault, J. P., Borgeat, P., Picard, S., and Corey, E. J. (1981) Pharmacological activity of leukotrienes A4, B4, C4, D4 on selected guinea pig, rat, rabbit and human smooth muscles. Prostaglandins Med. 7, 327–340.

    Article  PubMed  CAS  Google Scholar 

  • Skaug, N. and Detar, R. (1980) Indirect evidence for the importance of steady-state [K]0 in determining the extent of the effects of hyperpolarizing electrogenesis on vascular smooth muscle reactivity. Blood Vessels 17, 117–122.

    PubMed  CAS  Google Scholar 

  • Somlyo, A. P. and Somlyo, A. V. (1970) Vascular smooth muscle. II. Pharmacology of normal and hypertensive vessels. Pharmacol. Rev. 22, 249–353.

    PubMed  CAS  Google Scholar 

  • Spedding, M. and Cavero, I. (1984) “Calcium antagonists:” A class of drugs with a bright future. II. Determination of basic pharmacological properties. Life Sci 35, 575–587.

    Article  PubMed  CAS  Google Scholar 

  • Stephenson, R. P. (1956) A modification of receptor theory. Br. J. Pharmacol. 11, 379–393.

    CAS  Google Scholar 

  • Stone, P. H., Antman, E. M., Muller, J. E., and Braunwald, E. (1980) Calcium channel blocking agents in the treatment of cardiovascular disorders. II. Hemodynamic effects and clinical applications. Ann. Intern. Med. 93, 886–904.

    PubMed  CAS  Google Scholar 

  • Tallarida, R. J. and Jacob, L. S. (1979) Isolated Preparations: Dose-Response Data, in The Dose-Response Relation in Pharmacology Springer-Verlag, New York.

    Google Scholar 

  • Triggle, D. J. (1982) Counting Ca2+ channels? Trends Pharmacol. Sci. 3, 465–466.

    Article  CAS  Google Scholar 

  • Venter, J. C. (1979) High Efficiency coupling between beta–adrenergic receptors and cardiac contractility: Direct evidence for “spare” beta adrenergic receptors. Mol. Pharmacol. 16, 429–440.

    PubMed  CAS  Google Scholar 

  • Waud, D. R. (1968) Pharmacological receptors. Pharmacol. Rev. 20, 49–88.

    PubMed  CAS  Google Scholar 

  • Weiss, G. B. (1977) Calcium and Contractility in Vascular Smooth Muscle, in Advances in General and Cellular Pharmacology (Narahashi, T. and Bianchi, C. P., eds.) Plenum, New York. Williams, M. and Enna, S. J. (1986) The receptor: From concept to function. Ann. Rep. Med. Chem. 21, 211–235.

    Google Scholar 

  • Williams, M. and Enna, S.J. (1986) The receptor: From concept to function. Ann. Rep. Med. Chem. 21, 211–235.

    Article  CAS  Google Scholar 

Download references

Authors
  1. Frank R. Goodman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Drug Discovery Administration, Pharmaceuticals Division, Ciba-Geigy Corporation, Summit, New Jersey, USA

    Michael Williams

  2. Biomedical Research Department, Stuart Pharmaceuticals, ICI Americas Inc., Wilmington, Delaware, USA

    Jeffrey B. Malick

Rights and permissions

Reprints and permissions

Copyright information

© 1987 The Humana Press Inc.

About this chapter

Cite this chapter

Goodman, F.R. (1987). Use of Intact Tissue Preparations in the Drug Discovery Process. In: Williams, M., Malick, J.B. (eds) Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-4612-4828-6_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4612-4828-6_4

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-4612-9180-0

  • Online ISBN: 978-1-4612-4828-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation