Summary
Using computer-aided molecular modeling techniques to analyze models recently proposed for the receptor binding sites of dopaminergic agonists, we superimposed the chemical structures of various compounds that mimic the pharmacological behavior of dopamine, as well as inactive enantiomers, on a postulated three-dimensional frame of reference. We analyzed the vector directionalities of the lone pairs of the nitrogen common to these molecules, and the acidic hydrogen of phenols (in aminoindanes, aminotetralins, apomorphines,p-phenol-piperazines, octahydrobenzo(g)quinolines, octahydrobenzo(f)quinolines, and benzazepines) or of nitrogen (in ergoline-type compounds and related structures). This model, when expressed as distances from that of the reference compound pergolide, correlates with the dopaminergic binding affinity observed in compounds previously reported to act on the dopaminergic system in the central nervous system (CNS). The regression analysis of log KD with respect to the distances of the vectors of the acidic hydrogen support the hypothesis that these compounds bind to the receptor as donors in hydrogen bond formation.
Similar content being viewed by others
References
Cohen, N.C., In Testa, B. (Ed.) Advances in Drug Research, Vol 14, Academic Press, London, 1985, pp. 41–145.
Jolles, G. and Wooldridge, K.R.H., Drug Design: Fact or Fantasy?, Academic Press, London, 1984.
Nichols, D.E., In Kaiser, C. and Kebabian, J.W. (Eds.) Dopamine Receptors, ACS Symposium Series 224, American Chemical Society, Washington, D.C., 1983, pp. 201–218.
Kaiser, C., In Poste, G. and Crooke, S.T. (Eds.) Dopamine Receptor Agonists, Plenum Press, New York, 1984, pp. 87–137.
Kaiser, C. and Jain, T., Med. Res. Rev., 5 (1985) 145–229.
Kebabian, J.W. and Calne, D.B., Nature, 227 (1979) 93–96.
Goldberg, L.I. and Kohli, J.D., In Kaiser, C. and Kebabian, J.W. (Eds.) Dopamine Receptors, ACS Symposium Series 224, American Chemical Society, Washington, D.C., 1983, pp. 101–113.
Goldman, M.E. and Kebabian, J.W., In Dahl, S.G., Gram, L.F., Paul, S.M. and Potter, W.Z. (Eds.) Clinical Pharmacology in Psychiatry: Selectivity in Psychotropic Drug Action — Promises or Problems? Springer-Verlag, Heidelberg, 1986, pp. 201–213.
Olson, G.L., Cheung, H.-C., Morgan, K.D., Blount, J.F., Todaro, L., Berger, L., Davidson, A.B. and Boff, E., J. Med. Chem., 24 (1981) 1026–1034.
Van de Waterbeemd, H., Carrupt, P.-A. and Testa, B., J. Med. Chem., 29 (1986) 600–606.
McDermed, J.D., Freeman, H.S. and Ferris, R.M., In Usdin, E., Kopin, I.J. and Barchas, J. (Eds.) Catecholamines: Basic and Clinical Frontiers, Pergamon Press, New York, 1979, pp. 568–570.
Seeman, P., Pharmacol. Rev., 32 (1981) 229–313.
Wikstrom, H., Andersson, B., Sanchez, D., Lindberg, P., Arvidsson, L.-E., Johansson, A.M., Nilsson, J.L.G., Svensson, K., Hjorth, S. and Carlsson, A., J. Med. Chem., 28 (1985) 215–225.
Seeman, P., Watanabe, M., Grigoriadis, D., Tedesco, J.L., George, S.R., Svensson, U., Nilsson, J.L.G. and Neumeyer, J.L., Mol. Pharmacol., 28 (1985) 391–399.
Bach, N.J., Kornfeld, E.C., Clemens, J.A. and Smalstig, E.B., J. Med. Chem., 23 (1980) 812–814.
Bach, N.J., Kornfeld, E.C., Jones, N.D., Chaney, M.O., Dorman, D.E., Paschal, J.W., Clemens, J.A. and Smalstig, E.B., J. Med. Chem., 23 (1980) 481–491.
Cannon, J.G., Demopoulos, B.J., Long, J.P., Flynn, J.R. and Sharabi, F.M., J. Med. Chem., 24 (1981) 238–240.
Tripos Associates. St. Louis, Missouri 63117, SYBYL Molecular Modeling Manual.
Giesecke, J., Acta Crystallogr., Sect. B, 33 (1977) 302–303.
Camerman, N., Chan, L.Y.Y. and Camerman, A., Mol. Pharmacol., 16 (1979) 729–736.
Nelder, J.A. and Mead, R., Comput. J., 7 (1965) 308–313.
Vinter, J.G., Davis, A. and Saunders, M.R., J. Comput.-Aided Mol. Design, i (1987) 31–51.
Cannon, J.G., Dushin, R.G., Long, J.P., Ilhan, M., Jones, N.D. and Swartzendruber, J.K., J. Med. Chem., 28 (1985) 515–518.
Tripos Associates, St. Louis, Missouri 63117, DABYL Data Analysis Software.
Groll, C.J. and Rollema, H., J. Pharm. Pharmacol, 29 (1977) 153–156.
Wikstrom, H., Sanchez, D., Lindberg, P., Hacksell, U., Arvidsson, L.-E., Johansson, A.M., Thorberg, S.-O., Nilsson, J.L.G., Svensson, K., Hjorth, S., Clark, D. and Carlsson, A., J. Med. Chem., 27 (1984) 1030–1036.
Hamilton, W.C. and Ibers, J.A., Hydrogen Bonding in Solids, W.A. Benjamin, New York, 1968, pp. 14–16, 182–183.
Schaus, J.M. and Clemens, J.A., In Bailey, D.M. (Ed.) Annual Reports in Medicinal Chemistry, Vol. 20, Academic Press, London, 1985, pp. 41–50.
Clemens, J.A., Kornfeld, E.C., Phebus, L.A., Shaar, C.J., Smalstig, E.B., Cassady, J.M., Nichols, D.E., Floss, H.G. and Kelly, E., In Creighton, A.M. and Turner, S. (Eds.) The Chemical Regulation of Biological Mechanism, The Royal Society of Chemistry, Burlington House, London, 1982, pp. 167–180.
Lloyd, E.J. and Andrews, P.R., J. Med. Chem. 29 (1986) 453–462.
Olson, G.L., Cheung, H.-C., Chiang, E. and Berger, L., In Kaiser, C. and Kebabian, J.W. (Eds.) Dopamine Receptors, ACS Symposium Series 224, American Chemical Society, Washington, D.C., 1983, pp. 251–274.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tonani, R., Dunbar, J., Edmonston, B. et al. Computer-aided molecular modeling of a D2-agonist dopamine pharmacophore. J Computer-Aided Mol Des 1, 121–132 (1987). https://doi.org/10.1007/BF01676956
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01676956