Abstract
Purpose. Twelve synthetic spider toxin analogs were prepared in an effort to better understand the structure-activity relationships of the polyamine portion of argiotoxin-636 (Arg-636), a noncompetitive NMDA receptor (NMDAR) antagonist.
Methods. The l,13-diamino-4,8-diazatridecane portion of the side chain of Arg-636 was systematically modified in an effort to further our knowledge of the structural requirements for the alkyl linker spacing between the amine nitrogens. Systematic isosteric replacement of each of the amine nitrogens in the polyamine moiety with either oxygen or carbon provided a series of compounds which were evaluated in vitro for NMDAR antagonist activity.
Results. One-half of the heteroatoms found in Arg-636 were removed to provide analogs which maintained in vitro potency below 1 μM. However, these simplified analogs produced similar or more pronounced effects on the cardiovascular system than Arg-636 in vivo.
Conclusions. In this set of analogs, a minimum of three basic nitrogens in the side chain was required for maximum potency as NMDAR antagonists. Isosteric nitrogen substitutions in the polyamine chain reduced the in vitro potency of these analogs. An analog binding-conformation model was proposed to rationalize the inactivity of these isosterically substituted analogs.
Similar content being viewed by others
REFERENCES
B. C. Van Wagenen, E. G. DelMar, S. T. Moe, S. M. Shimizu, D. L. Smith, R. M. Barmore, R. Trovato, J. L. Rhodes, A. P. Miaullis, M. F. Balandrin, L. D. Artman, N. Alasti, and A. L. Mueller. 209th American Chemical Society National Meeting, MEDI 134, April 2–6, 1995.
A. L. Mueller, B. C. Van Wagenen, E. G. Delmar, M. F. Balandrin, S. T. Moe, and L. D. Artman. PCT Intl. Appl. WO 95/21612, August 17, 1995. Chem. Abstr. 123(23): P 306618t (1995). U.S. Pat. Appl. 14,813, February 8, 1994.
A. L. Mueller, L. D. Artman, Y. Chien, J. L. Raszkiewicz, N. Alasti, E. G. DelMar, B. C. Van Wagenen, S. T. Moe, M. F. Balandrin, D. L. Smith, S. M. Shimizu, J. L. Rhodes, R. Trovato, and R. M. Barmore. Keystone Symposia on Molecular and Cellular Biology: Ion Channels as Theraputic Targets, Tamarron, CO, February 4–10, 1996.
N. A. Saccomano, R. A. Volkmann, H. Jackson, and T. N. Parks. Annu. Rep. Med. Chem. 24:287–293 (1989).
D. L. Smith, S. T. Moe, L. D. Artman, and A. L. Mueller. Joint 50th Northwest/12th Rocky Mountain Regional American Chemical Society Meeting, No. 221, June 14–16 (1995).
S. T. Moe, D. L. Smith, L. D. Artman, and A. L. Mueller. Joint 50th Northwest/12th Rocky Mountain Regional American Chemical Society Meeting, No. 222, June 14–16 (1995).
A. L. Mueller, R. Roeloffs, and H, Jackson. In G. A. Cordell (Ed.), The Alkaloids, Academic Press, NY, 1995, Vol. 46, pp. 63–94.
A. Schäfer, A. Benz, W. Fiedler, A. Guggisberg, S. Beinz, and M. Hesse. In G. A. Cordell and A. Brossi (Eds.), The Alkaloids: Chemistry and Pharmacology, Vol. 45, Academic Press, NY, 1993, pp. 1–125.
E. V. Grishin, T. M. Volkova, A. S. Arseniev, O. S. Reshetova, and V. V. Onopreinko. Bioorg. Khim. 12:1121–1124 (1986).
A. Bateman, P. Boden, A. Dell, I. R. Duce, D. L. J. Quicke, and P. N. R. Usherwood. Brain Res. 339:237–244 (1989).
T. Budd, P. Clinton, A. Dell, I. R. Duce, S. J. Johnson, D. L. J. Quicke, G. W. Taylor, P. N. R. Usherwood, and G. Usoh. Brain Res. 448:30–39 (1988).
J. E. Watkins and R. H. Evans. Annu. Rev. Pharmacol. Toxicol. 21:165–204 (1981).
A. C. Foster and G. E. Fagg. Brain Res. Rev. 1:103–104 (1984).
A. L. Mueller, B. C. Albenzi, A. H. Ganong, L. S. Reynolds, and H. Jackson. Synapse 9:244–250 (1991).
R. W. Ransom and N. L. Stec. J. Neurochem. 51:830 (1988).
D. W. Choi. Neuron 1:623–634 (1988).
A. B. MacDermott, M. L. Mayer, G. L. Westbrook, S. J. Smith, and J. L. Barker. Nature 321:519–522 (1986).
F. A. Schanne, A. B. Kane, E. E. Young, and J. L. Farber. Science 206:700–702 (1979).
B. S. Meldrum and A. G. Chapman. In G. L. Collingridge and J. C. Watkins (Eds.), The NMDA Receptor, 2nd ed., Oxford University Press, NY, 1994, pp. 457–468.
P. L. Feldman, O. W. Griffith, and D. J. Stuehr. Chem. Eng. News 71:26–38 (1993).
P. A. Krapcho and C. S. Kuell. Synth. Commun. 20:2559–2564 (1990).
T. N. Parks, L. D. Artman, N. Alasti, and E. F. Nemeth. Brain Res. 552:13–22 (1991).
K. Williams, C. Romano, and P. B. Molinoff. Molec. Pharmacol. 36:575–581 (1989).
O. H. Lowry, N. H. Rosenbrough, A. C. Farr, and R. J. Randall. J. Biol. Chem. 193:265–275 (1951).
T. L. Shih, J. R. Sanchez, and H. Mrozik. Tetrahedron Lett. 28:6015–6018 (1987).
M. E. Adams, R. L. Carney, F. E. Enderlin, E. T. Fu, M. A. Jarema, J. P. Li, C. A. Miller, D. A. Schooley, M. J. Shapiro, and V. J. Venema. Biochem. Biophys. Res. Commun. 148:678–683 (1987).
É. A. Elin, B. F. de Masedo, V. V. Onoprienko, N. E. Osokina, and O. B. Tikhomirova. Bioorg. Khim. 14:704–706 (1988) (translation by Plenum Publishing Co., 1989).
V. J. Jasys, P. R. Kelbaugh, D. M. Nason, D. Phillips, N. A. Saccomano, and R. A. Volkmann. Tetrahedron Lett. 29:6223–6226 (1988).
S.-K. Choi and K. Nakanishi. Tetrahedron 49:5777–5790 (1993).
N. Anis, S. Sherby, R. Goodnow, Jr., M. Niwa, K. Konno, T. Kallimopoloulos, R. Bukownik, K. Nakanishi, P. Usherwood, A. Eldefrawi, and M. Eldefrawi. J. Pharmacol. Exptl. Therap. 254:764–773 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Moe, S.T., Smith, D.L., Chien, Y.(. et al. Design, Synthesis, and Biological Evaluation of Spider Toxin (Argiotoxin-636) Analogs as NMDA Receptor Antagonists. Pharm Res 15, 31–38 (1998). https://doi.org/10.1023/A:1011988317683
Issue Date:
DOI: https://doi.org/10.1023/A:1011988317683