Azaindole derivatives with high affinity for the dopamine D4 receptor: Synthesis, ligand binding studies and comparison of molecular electrostatic potential maps (original) (raw)

Abstract

Piperazinylmethyl substituted pyrazolo[1,5-a]pyridines and related heterocycles were synthesized and found to recognize selectively the dopamine D4 receptor. For the most potent derivative 10d a Ki value of 2.0 nM was observed. SAR studies including the comparison of molecular isopotential surfaces were performed. © 1998 .Elsevier Science Ltd. All rights reserved.

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References (27)

  1. The Dopamine Receptors; Neve, K.A.; Neve, R.L., Ed.; Humana Press: Totowa, New Jersey, 1997.
  2. Sibley, D.R.; Monsma, Jr., F.J. TiPS 1992, 13, 61. Sokoloff, P.; Schwartz, J.-C. TiPS 1995, 16, 270.
  3. Van Tol, H.H.M.; Bunzow, J.R.; Guan, H.-C., Sunahara, R.K.; Seeman, P., Niznik, H.B.; Civelli, O. Nature 1991, 350, 610.
  4. Strange, P.G. TiPS 1994, 15, 317 and references cited therein.
  5. For review: Liegeois, J.-F.; Eyrolles, L.; Bruhwyler, J.; Delarge, J. Curr. Med. Chem. 1998, 5, 77.
  6. For review: Steiner, G.; Bach, A.; Bialojan, S.; Greger, G.; Hege, H.-G.; H6ger, T.; Jochims, K.; Mun- schauer, R.; Neumann, B.; Teschendorf, H.-J.; Traut, M.; Unger, L.; Gross, G. Drugs Fut. 1998, 23, 191
  7. For review: Kulagowski, J.J.; Patel, S. Curr. Pharm. Design 1997, 3, 355 and references cited therein.
  8. Gmeiner, P.; Mierau, J.; H6fner, G.; Arch. Pharm. (Weinheim) 1992, 325, 57.
  9. Gmeiner, P.; Sommer, J.; Mierau, J.; H6fner, G. Bioorg. Med. Chem. Lett. 1993, 3, 1477.
  10. Kulagowski, J.J.; Broughton, H.B.; Curtis, N.R.; Mawer, I.M.; Ridgill, M.P.; Baker, R.; Emms, F.; Freedman, S.B.; Marwood, R.; Patel, Sh.; Patel, Sm.; Ragan, C.I.; Leeson, P.D.J. Med. Chem. 1996, 39, 1941.
  11. Bristow, L.J.; Kramer, M.S.; Kulagowski, J.; Patel, S.; Ragan, C.I.; Seabrook, G.R. TiPS 1997, 18, 186.
  12. Huisgen, R.; Grashey, R.; Krischke, R. Tetrahedron Lett. 1962, 387.
  13. Gmeiner, P.; Schtinemann, J. Arch. Pharm. (Weinheim) 1988, 321,517.
  14. Gmeiner, P.; Sommer, J. Arch. Pharm. (Weinheim) 1988, 321,505.
  15. Wright, Jr., W.B.J. Org. Chem. 1962, 27, 1042.
  16. Experimental details for the preparation of 10d: To a solution of 6 (100mg, 0.5 mmol) in THF (10ml) was added LiA1H 4 (0.5ml of 1M solution in THF, 0.5mmol) at RT. After stirring for 30 min, the mixture was warmed to 60°C. Then, 9 (150mg, 0.8mmol) dissolved in THF (4ml) was added dropwise during a period of 20 min and stirring was continued for another 15 rain. The mixture was cooled to RT, treated with sat. aq. NaHCO 3 and extracted with CHEC12.The organic layer was dried (MgSO4) , evaporated and the residue purified by flash chromatography (CH2C12 / MeOH 95:5) to give 10d (59mg, 36%) as a white solid. Analytical data of 10d: m.p.: 160°C. 1H NMR (CDCI3, 360 MHz): 5 (ppm) = 2.60-2.63 (m, 4H, 2x NCHECH2), 3.14-3.17 (m, 4H, 2x CH C2. . C_HH2N), 3.75 (s, 2H, ArCH2N), 6.75 (ddd, 3J=7.0/7.0 Hz 4j= 1.4, 1 H, 6-H), 6.79-6.84 (m, 2H, Ph), 7.10 (ddd, 3J=8.5/7.0 Hz 4J=0.8 Hz, 1H, 5-H), 7.16-7.20 (m, 2H, Ph), 7.63 (br d, J~8.5
  17. Hz, 1H, 4-H), 7.91 (s, 1H, 2-H), 8.44 (br d, J=7.0 Hz, 7-H). 13C NMR (CDC13, 60 MHz): 5(ppm) 49.1, 49.1, 52.1, 52.7, 52.7, 106.8, 111.6, 117.1,117.1,117.3, 122.8, 124.4, 128.7, 128.9, 128.9, 139.1, 142,4, 149.9. El-MS m/z: 326 (M÷), 328 (M+). IR (film): 2941, 2822, 1633, 1595, 1496, 1234 cm -1. C~8H19C1N4(326.8): Calc.: C 66.15 H 5.86 N 17.15; Found: C 65.97 H 5.94 N 16.92.
  18. Hanson, R.N.; Hariharan, S.; Astik, R. J. Heterocyclic Chem. 1985, 22, 47.
  19. Huisgen, R.; Grashey, R.; Krischke, R. Liebigs Ann. Chem. 1977, 506.
  20. Tominaga, Y.; Ichihara, Y.; Moil, T.; Kamio, C.; Hosomi, A. J. Heterocyclic. Chem. 1990, 27, 263.
  21. Lombardino, J.G.J. Org. Chem. 1965, 30, 2403.
  22. Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992, 40, 1170.
  23. Sokoloff, P.; Andrieux, M.; Besancon, R.; Pilon, C.; Martres, M.-P.; Giros, B.; Schwartz, J.-C. Eur. J. Pharmacol. 1992, 225,331.
  24. Asghari, V.; Sanyal, S.; Buchwaldt, S.; Paterson, A.; Jovanovic, V.; Van Tol, H.H.M.J.Neurochem.1995, 65, 1157.
  25. Ohnmacht, U.; Trtinkle, C.; Mohr, K.; Gmeiner, P. Pharmazie, 1998, in press, and references cited therein.
  26. Data are the means of two to three experiments performed in triplicate at eight different concentrations.
  27. Ab initio calculations and visualizations have been done using the program package PC SPARTAN PLUS (Wavefunction, Inc.).