Trends in the Pharmacokinetics of Drug-Receptor Interactions

  • David E. Schafer
Part of the NATO ASI Series book series (NSSA, volume 221)


The opportunity to speak about receptor mathematics on the ancient and beautiful island of Sicily is both a challenge and an inspiration. Sicily, after all, was the home both of the mad philosopher Empedocles of Agrigento (c. 495–35 BCE), who might be said to have first dimly envisioned something like receptors [Kirk, Raven, and Schofield, 1983], and of the greatest mathematician up to the time of Isaac Newton, Archimedes of Syracusa (d. 212 BCE), who, unlike his predecessors, did not disdain to use approximate methods to achieve a practical result [Struik, 1987]


Positron Emission Tomography Insulin Receptor Closed Duration Positive Cooperativity Negative Cooperativity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abbott, A.J., and, G.L. Nelsestuen, 1988. The collisional limit: an important consideration for membrane-associated enzymes and receptors. FASEB J. 2: 2858.Google Scholar
  2. Andreasen, N.C., R. Carson, M. Diksic, A. Evans, L. Farde, A. Gjedde., A. Hakim, S. Lal, N. Nair, G. Sedvall, L. Tune, and D. Wong, 1988. Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum. Schizophrenia Bull. 14: 471.Google Scholar
  3. Artom, C., G. Sarzana, C. Perrier, M. Santangelo, and E. Segré, 1937. Arch. Internat. Physiol. 45:32. Cited in Kamen, M.D., 1957, “Isotopic Tracers in Biology,” Academic Press, New York.Google Scholar
  4. Berg, H.C. and E.M. Purcell, 1977. Physics of chemoreception. Biophys. J. 24: 193.CrossRefGoogle Scholar
  5. Brodde, O.-E., 1989. ß-Adrenoceptors. In “Receptor Pharmacology and Function” (Williams, M., Glennon, R.A., and Timmermans, P.B.M.W.M., eds.), Chapter 8. Marcel Dekker, New York.Google Scholar
  6. Castillo, J. del, and B. Katz, 1957. Interaction at end-plate receptors between different choline derivatives. Proc. Roy. Soc. (London) B 146: 369.CrossRefGoogle Scholar
  7. Chance, B. 1943. The kinetics of the enzyme-substrate compound of peroxidase. J. Biol. Chem. 151: 553.Google Scholar
  8. Chen, W.S., C. S. Lazar, K. A. Lund, J. B. Welsh, C.-P. Chang, G. M. Walton, C. J. Der, H. S. Wiley, G. N. Gill, and M.G. Rosenfeld, 1989. Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation. Cell 59: 33.PubMedCrossRefGoogle Scholar
  9. Cheng, Y.-C., and W.H. Prusoff, 1973. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22: 3309.Google Scholar
  10. Claudio, T., W. N. Green, D. S. Hartmann, D. Hayden, H. L. Paulson, F. J. Sigworth, S. M. Sine, and A. Swedlund, 1987. Genetic reconstruction of functional acetylcholine receptor channels in mouse fibroblasts. Science 238: 1688.PubMedCrossRefGoogle Scholar
  11. Cohen, N.C., J. M. Blaney, C. Humblet, P. Gund, and D.C. Barry, 1990. Molecular modeling software and methods for medicinal chemistry. J. Med. Chem. 33: 883.PubMedCrossRefGoogle Scholar
  12. Colquhoun, D. and A.G. Hawkes, 1977. Relaxations and fluctuations of membrane currents that flow through drug operated channels. Proc. Roy. Soc. (London) B 199: 231.CrossRefGoogle Scholar
  13. Colquhoun, D. and A.G. Hawkes, 1981. On the stochastic properties of single ion channels. Proc. Roy. Soc. (London) B211: 205.CrossRefGoogle Scholar
  14. Cuatrecasas, P., and S. Jacobs ed., 1990. “Insulin”, Vol. 92, Handbook of Experimental Pharmacology, Springer-Verlag, Berlin.Google Scholar
  15. DeLisi, C., 1980. The biophysics of ligand-receptor interaction. Q. Rev. Biophys. 103: 32.Google Scholar
  16. De Meyts, P. E. Van Obberghen, and J. Roth, 1978. Mapping of the residues responsible for the negative cooperativity of the receptor-binding region of insulin. Nature 273: 504.PubMedCrossRefGoogle Scholar
  17. Ehrlich, P., 1909. Ueber den jetzigen Stand der Chemotherapie. Ber. Dtsch. Chem. Ges. 42: 17.CrossRefGoogle Scholar
  18. Eigen, M., 1954. Methods for investigation of ionic reactions in aqueous solutions with half-times as short as 10–9 sec. Discuss. Faraday Soc. 17: 194.CrossRefGoogle Scholar
  19. Epps, D.E., H. Schostarez, C. V. Argoudelis, R. Poorman, J. Hinzmann, T. K. Sawyer, and F. Mandel, 1989. An experimental method for the determination of enzyme-competitive inhibitor dissociation constants from displacement curves: application to human renin using fluorescence energy transfer to a systhetic dansylated inhibitor peptide. Anal. Biochem. 181: 172.PubMedCrossRefGoogle Scholar
  20. Farde, L., F. A. Wiesel, H. Hall, C. Halldin, S. Stone-Elander, and G. Sedvall, 1987. No D2 receptor increase in PET study of schizophrenia. Arch. Gen. Psychiat. 44: 671.PubMedCrossRefGoogle Scholar
  21. Fatt, P., and B. Katz, 1952. Spontaneous subthreshold activity at motor nerve endings. J. Physiol. (London) 117: 109.Google Scholar
  22. Freissmuth, M., P. J. Casey, and A.G. Gilman, 1989. G proteins control diverse pathways of transmembrane signaling. FASEB J. 3: 2125.PubMedGoogle Scholar
  23. Gammeltoft, S., 1984. Insulin receptors: binding kinetics and structure-function relationship of insulin. Physiol. Rev. 64: 1321.PubMedGoogle Scholar
  24. Gilbert, W., 1991. Towards a paradigm shift in biology. Nature 349: 99.PubMedCrossRefGoogle Scholar
  25. Gjedde, A., and D.F. Wong, 1991. Dopamine D2 receptors in schizophrenia: hypothetical reconciliation of PET results. Abstr. Proc. “Brain 91” (Miami FL, June 1–6, 1991). J. Cereb. Blood Flow Metab. 31 (Supp. 1).Google Scholar
  26. Goldstein, G., R. G. Posner, D. C. Torney, J. Erickson, D. Holowka, and B. Baird, 1989. Competition between solution and cell surface receptors for ligand: dissociation of hapten bound to surface antibody in the presence of solution antibody. Biophys. J. 56: 955.PubMedCrossRefGoogle Scholar
  27. Gu, J.-L., I. D. Goldfine, J. R. Forsayeth, and P. De Meyts, 1988. Reversal of insulin-induced negative cooperativity by monoclonal antibodies that stabilize the slowly dissociating state of the insulin receptor. Biochem. Biophys. Res. Commun. 150: 694.PubMedCrossRefGoogle Scholar
  28. Hamill, O.P., A. Marty, E. Neher, B. Sakmann, and F.J. Sigworth, 1981. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrance patches. Pfluegers Arch. 391: 85.CrossRefGoogle Scholar
  29. Hausdorff, W.P., M. G. Caron, and R.J. Lefkowitz, 1990. Turning off the signal: desensitization of ß-adrenergic receptor function. FASEB J. 4: 2281.Google Scholar
  30. Hevesy, G., and L. Hahn, 1941. Kgl. Danske Videnskab. Selskab, Biol. Medd. 16: 1.Google Scholar
  31. Cited in Kamen, M.D., 1957. “Isotopic Tracers in Biology.” Academic Press, New York.Google Scholar
  32. Horovitz, A., and A. Levitzky, 1987. An accurate method for determination of receptor-ligand and enzyme-inhibitor dissociation constants from displacement curves. Proc. Natl. Acad. Sci. USA 84: 6654.PubMedCrossRefGoogle Scholar
  33. Hruby, V.J., and C.A. Gehrig, 1989. Recent developments in the design of receptor specific opioid peptides. Med. Res. Rev. 9: 343.PubMedCrossRefGoogle Scholar
  34. Huang, S.-C., and M.E. Phelps, 1986. Principles of tracer kinetic modeling in position emission tomography and autoradiography.In: “Positron Emission Tomography and Autoradiography: Principles and Applications” (Phelps, M.E., Mazziotta, J.C., and Schelbert, H.R., eds.), Chapter 7. Raven Press, New York.Google Scholar
  35. Imoto, K., C. Busch, B. Sakmann, M. Mishina, T. Konno, J. Nakai, H. Bujo, Y. Mori, K. Fukuda, and S. Numa, 1988. Rings of negatively charged amino acids determine the acetylcholine receptor conductance. Nature 335: 645.PubMedCrossRefGoogle Scholar
  36. Katz, B., and R. Miledi, 1972. The statistical nature of the acetylcholine potential and its molecular components. J. Physiol. (London) 224: 665.Google Scholar
  37. Kawasaki, A.M., R. J. Knapp, T. H. Kramer, W. S. Wire, O. S. Vasquez, H. I. Yamamura, T. F. Burks, and F.J. Hruby, 1990. Design and synthesis of highly potent and selective cyclic dynorphin A analogues. J. Med. Chem. 33: 1874.PubMedCrossRefGoogle Scholar
  38. Kirk, G.S., J. E. Raven, and M. Schofield, 1983. “The Presocratic Philosophers.” Cambridge University Press, Cambridge.Google Scholar
  39. Lefkowitz, R.J., B. K. Kobilka, and M.G. Caron, 1989. The new biology of drug receptors. Biochem. Pharmacol. 38: 2941.PubMedCrossRefGoogle Scholar
  40. Levy, J.R., and J.M. Olefsky, 1990. Receptor-mediated internalization and turnover. In: “Insulin” (Cuatrecasas, P., and S. Jacobs, eds.), Vol. 92, Chapter 12. Handbook of Experimental Pharmacology, Springer-Verlag, Berlin.Google Scholar
  41. Limbird, L.E., 1986. “Cell Surface Receptors: A Short Course on Theory and Methods.” Martinus Nijhoff, Boston.Google Scholar
  42. Lund, K.A., L. K. Opresko, C. Starbuck, B. J. Walsh, and H.S. Wiley, 1990. Quantitative analysis of the endocytic system involved in hormone-induced receptor internalization. J. Biol. Chem 265: 15–713.Google Scholar
  43. Marshall, G.R. 1987. Computer-aided drug design. Ann. Rev. Pharmacol. Toxicol. 27: 193.CrossRefGoogle Scholar
  44. Marshall, G.R., and R.D. Cramer, 3rd, 1988. Three-dimensional structure-activity relationships. Trends Pharmacol. Sci. 9: 285.PubMedCrossRefGoogle Scholar
  45. Martin, Y.C., and E. Danaher, 1989. Molecular modeling of receptor-ligand interactions. In: “Receptor Pharmacology and Function” (Williams, M., Glennon, R.A., and Timmermans, P.B.M.W.M. eds.), Chapter 6. Marcel Dekker, New York.Google Scholar
  46. McLane, J.A., and J.M. Pawelek, 1988. Receptors for B-melanocyte-stimulating hormone exhibit positive cooperativity in synchronized melanoma cells. Biochem. 27: 3743.CrossRefGoogle Scholar
  47. Mercier, G.A., Jr., R. Osman, and H. Weinstein, 1988. Role of primary and secondary protein sturcture in neurotransmitter receptor activation mechanisms. Protein Eng. 2: 261.PubMedCrossRefGoogle Scholar
  48. Mercier, G.A., Jr., R. Osman, R., and H. Weinstein, 1989. A molecular theoretical model of recognition and activation at a 5-HT receptor. Prog. Clin. Biol. Res. 289: 399.Google Scholar
  49. Munson, P.J., and D. Rodbard, 1988. An exact correction to the “Cheng-Prusofr correction. J. Recept. Res. 8: 533.PubMedGoogle Scholar
  50. Nathanson, N.M., and T.K. Harden ed., 1990. “G Proteins and Signal Transduction”. 43rd Ann. Symp., Soc. Gen. Physiol. Rockefeller Univ. Press, New York.Google Scholar
  51. Neher, E., and B. Sakmann, 1976. Single channel currents recorded from membrane of denervated frog muscle fibres. Nature 260: 799.PubMedCrossRefGoogle Scholar
  52. Ogden, D.C. and D. Colquhoun, 1965. Ion channel block by acetylcholine, carbachol, and suberyldicholine at the frog neuromuscular junction. Proc. Roy. Soc. (London) B225: 329.Google Scholar
  53. Perun, T.J., and C.L. Probst, 1989. “Computer-Aided Drug Design: Methods and Applications”. Dekker, New York.Google Scholar
  54. Phelps, M.E., J. C. Mazziotta, and H.R. Schelbert, 1986. “Positron Etnission Tomography and Autoradiography: Principles and Applications”. Raven Press, New York.Google Scholar
  55. Roth, R.A., 1990. Insulin receptor structure. In: “Insulin” (Cuatrecasas, P. and Jacobs, S. eds.). Handbook of Experimental Pharmacology, Vol. 92, Chapter 9. Springer-Verlag, Berlin.Google Scholar
  56. Roughton, F.J.W., A. B. Otis, and R.L.J. Lyster, 1955. The determination of the individual equilibrium constants of the four intermediate reactions between oxygen and sheep haemoglobin. Proc. Roy. Soc. (London) B144: 29.CrossRefGoogle Scholar
  57. Schafer, D.E., 1983. Measurement of Ligand-Receptor Binding: Theory and Practice. In: “Tracer Kinetics and Physiologic Modeling” ( Lambrecht, R.M. and Rescigno, A., eds.), page 445. Springer-Verlag, Berlin.Google Scholar
  58. Sine, S.M., T. Claudio, and F.J. Sigworth, 1990. Activation of Torpedo acetylcholine receptors expressed in mouse fibroblasts: Single channel current kinetics reveal distinct agonist binding affinities. J. Gen. Physiol., 96: 395.PubMedCrossRefGoogle Scholar
  59. Sonne, O., 1988. Receptor-mediated endocytosis and degradation of insulin. Physiol. Rev. 68: 1129.PubMedGoogle Scholar
  60. Starbuck, C., H. S. Wiley, and D.A. Lauffenburger, 1990. Epidermal growth factor binding and trafficking dynamics in fibroblasts: Relationship to cell proliferation. Chem. Eng. Sci. 45: 2367.CrossRefGoogle Scholar
  61. Stephenson, R.P. 1956. A modification of receptor theory. Br. J. Pharm. Chemother. 11: 379.Google Scholar
  62. Stix, G., 1991. Reach out: Touch is added to virtual reality simulations. Sci. Amer. 264: 134.PubMedCrossRefGoogle Scholar
  63. Struik, D.J., 1987. “A Concise History of Mathematics”, Dover, New York.Google Scholar
  64. Tank, D.W., R. L. Huganir, P. Greengard, and W.W. Webb, 1983. Patch-recorded single-channel currents of the purified and reconstituted Torpedo acetylcholine receptor. Proc. Nat. Acad. Sci. (USA) 80: 5129.CrossRefGoogle Scholar
  65. Tilton, R.F., Jr., U. C. Singh, I. D. Kuntz, Jr., and P.A. Kollman, 1988. Protein-ligand dynamics. A 96 picosecond simulation of a myoglobin-xenon complex. J. Mol. Biol. 199: 195.PubMedCrossRefGoogle Scholar
  66. Titeler, M., 1989. Receptor binding theory and methodology. In: “Receptor Pharmacology and Function” (Williams, M., Glennon, R.A., and P.B.M.W.M. Timmermans eds.), Chapter 2. Marcel Dekker, New York.Google Scholar
  67. Weiss, E.R., D. J. Kelleher, C. W. Woon, S. Soparkar, S. Osawa, L. E. Heasley, and G.L. Johnson, 1988. Receptor activation of G proteins. FASEB J. 2: 2841.Google Scholar
  68. Wiley, H.S. 1985. Receptors as models for the mechanisms of membrane protein turnover and dynamics. Curr. Top. Membr. Trans. 24: 369.CrossRefGoogle Scholar
  69. Wiley, H.S. 1988. Anomalous binding of epidermal growth factor to A431 cells is due to the effect of high receptor densities and a saturable endocytic system. J. Cell. Biol. 107: 801.PubMedCrossRefGoogle Scholar
  70. Wiley, H.S. and D.D. Cunningham, 1981. A steady state model for analyzing the cellular binding, internalization and degradation of polypeptide ligands. Cell 25: 433.PubMedCrossRefGoogle Scholar
  71. Wiley, H.S. and D.D. Cunningham, 1982. The endocytic rate constant: A cellular parameter for quantitating receptor-mediated endocytosis. J. Biol. Chem. 257: 4222.PubMedGoogle Scholar
  72. Williams, M., R. A. Glennon, and P.B.M.W.M. Timmermans, 1989. “Receptor Pharmacology and Function”. Marcel Dekker, New York.Google Scholar
  73. Wong, D.F., H. N. Wagner, Jr., L. E. Tune, R. F. Dannals, G. D. Pearlson, J. M. Links, D. A. Tamminga, E. P. Broussole, H. T. Raven, A. A. Wilson, J. K. T. Toung, J. Malat, J. A. Williams, L. A. O’Tuama, S. H. Snyder, J. J. Kuhar, and A. Gjedde, 1986a. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234: 1558.Google Scholar
  74. Wong, D.F., A. Gjedde, H. N. Wagner, Jr., R. F. Dannals, K. H. Douglass, J. M. Link, and M.J. Kuhar, 1986b. Quantification of neuroreceptors in the living human brain: II. Inhibition studies of receptor density and affinity. J. Cereb. Blood Flow Metab. 6: 147.Google Scholar
  75. Wong, D.F., A. Gjedde, D. Young, T. Young, L. Tune, E. Shaya, G. Pearlson, B. Chan, D. Burkhardt, P. D. Wilson, R. F. Dannals, A. A. Wilson, H. T. Ravert, T. K. Natarajan, and H.N. Wagner, Jr., 1991. Elevated endogenous dopamine concentrations in striatum of psychotic patients in vivo. Abstr. Proc. “Brain 91” (Miami, Florida, June 1–6, 1991). J. Cereb. Blood Flow Metab. 11 (Supp. 1).Google Scholar
  76. Young, A.B., K. Frey, and B.W. Agranoff, 1986. Receptor assays: in vitro and in vivo. In: “Positron Emission Tomography and Autoradiography: Principles and Applications” ( M. E. Phelps, J. C. Mazziotta, and H.R. Schelbert, eds.). Raven Press, New York.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • David E. Schafer
    • 1
  1. 1.Department of Veterans Affairs Medical CenterWest HavenUSA

Personalised recommendations