S. T. Moe et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2411±2415
2415
Compound 4a (S-methyl) showed potent, functional in
vitro NMDA receptor antagonist activity (IC50 89 nM)
with an IC50 value similar to that of its unbranched
counterpart (1, IC50 63 nM). The more-active S enan-
tiomer (4a, IC50 89 nM) was one order of magnitude
more potent than the R stereoisomer (4b) in the RCGC
NMDA receptor assay and approximately six-times
more potent than 4b at displacing radioligand from
MK-801-labeled binding sites. Similarly, the S enantio-
mer (4a) was found to be three times more potent in
vivo against audiogenic seizures than the R enantiomer
(4b) and twofold more potent that the racemate (4). Full
details of the structure±activity relationships, chemical
syntheses, molecular modeling, and pharmacological
studies of the diphenylpropylamines as NMDA antago-
nists will be the subject of future publications.
ton, I. American Academy of Neurology Annual Meeting,
Minneapolis, MN, 25 April, 1998.
12. Moe, S. T.; Shimizu, S. M.; Smith, D. L.; Van Wagenen,
B. C.; DelMar, E. G.; Balandrin, M. F.; Chien, Y.; Raszkie-
wicz, J. L.; Artman, L. D.; Mueller, A. L. Bioorg. Med. Chem.
Lett. 1999, 9, 1915.
13. The Merck Index: An Encyclopedia of Chemicals, Drugs,
and Biologicals, 12th ed.; Budavari, S., O'Neil, M. J., Smith,
A., Heckelman, P. E., Kinneary, J. F., Eds.; Merck Research
Laboratories: Whitehouse Station, NJ, 1998.
14. Robertson, D. W.; Krushinski, J. H.; Fuller, R. W.;
Leander, J. D. J. Med. Chem. 1988, 31, 1412.
15. Enders, D.; Schubert, H.; Nubling, C. Angew. Chem., Int.
Ed. Engl. 1986, 25, 1109.
16. Denmark, S. E.; Weber, T.; Piotrowski, D. W. J. Am.
Chem. Soc. 1987, 109, 2224.
17. Enders, D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173.
18. Compound 4a: ꢀ90% ee/NMR (urea derivative); mp 143±
23
145 ꢁC; [a]2D3 4.0ꢁ (c 0.5, MeOH), [a]
16ꢁ (c 0.5, MeOH);
365
1H NMR (300 MHz, CDCl3/methanol-d4 [3:1]) d 1.35 (d, 3H,
CH3), 2.23 (m, 1H, CH2), 2.58 (m, 1H, CH2), 3.14 (bs, 1H,
CHNH+3 ), 4.25 (t, 1H, Ar2CH), 7.25±6.83 (m, 8H, ArH), 8.31
(bs, 3H, NH+3 ); GC/MS tR 7.02 min, m/z 261 (M+). Com-
References and Notes
pound 4b: ꢀ94% ee/NMR (urea derivative); mp 119±135 ꢁC;
23
1. The NMDA Receptor, 2nd ed.; Collingridge, G. L., Wat-
kins, J. C., Eds.; Oxford University: New York, 1994, passim.
2. Parsons, C. G.; Danysz, W.; Quack, G. Drug News Per-
spect 1998, 11, 523.
3. Mueller, A. L.; Van Wagenen, B. C.; DelMar, E. G.;
Balandrin, M. F.; Moe, S. T.; Artman, L. D. PCT Internatl.
Appl. WO 95/21,612 (1995); Chem. Abstr. 123, P 306618t.
4. Mueller, A. L.; Moe, S. T.; Balandrin, M. F.; DelMar, E.
G.; Van Wagenen, B. C.; Artman, L. D.; Barmore, R. M.;
Smith, D. L. PCT Internatl. Appl. WO 96/40,097 (1996);
Chem. Abstr. 126, P 143970x.
5. Moe, S. T.; Smith, D. L.; Chien, Y.; Raskiewicz, J. L.;
Artman, L. D.; Mueller, A. L. Pharm. Res. 1998, 15, 31.
6. Mueller, A. L.; Moe, S. T.; Balandrin, M. F.; Van
Wagenen, B. C.; DelMar, E. G.; Artman, L. D.; Barmore, R.
M.; Smith, D. L. PCT Internatl. Appl. WO 97/46,511 (1997);
Chem. Abstr. 128, P 61341v.
7. Balandrin, M. F.; Van Wagenen, B. C.; DelMar, E. G.;
Artman, L. D.; Mueller, A. L. Proceedings of the 37th Annual
Meeting of the American Society of Pharmacognosy, University
of California, Santa Cruz, CA, 27±31 July 1996, O19.
8. Van Wagenen, B. C.; Balandrin, M. F.; DelMar, E. G.;
Artman, L. D.; Mueller, A. L. 212th National Meeting of the
American Chemical Society, Orlando, FL, 25±29 August 1996,
ORGN 273.
[a]2D3 +6.4ꢁ (c 0.5, MeOH), [a]
NMR data were consistent with those obtained from NMR
+19ꢁ (c 0.5, MeOH); 1H
365
experiments with the S enantiomer.
19. Juaristi, E.; Murer, P.; Seebach, D. Synthesis 1993, 3, 1243.
20. Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,
183.
21. Following a reported method,22 primary cultures of
RCGCs obtained from 8-day-old rats were incubated with
fura-2/acetoxymethylester to measure intracellular calcium
concentrations. A combination of NMDA (50 mM) and gly-
cine (1 mM) was used as the stimulus to elicit calcium in¯ux.
Multiple cumulative concentration±response curves were per-
formed for each antagonist tested. IC50 values were deter-
mined by logit analysis.
A minimum of ®ve dierent
concentrations of each test substance were used in the deter-
mination of each IC50.
22. Parks, T. N.; Artman, L. D.; Alasti, N.; Nemeth, E. F.
Brain Res. 1991, 552, 13.
23. Following a literature procedure,24 cerebral cortex tissue
was harvested from male Sprague±Dawley rats. Samples were
incubated with [3H]-MK-801, glycine, l-glutamic acid, and
varying concentrations of displacer. Nonspeci®c binding was
determined by the inclusion of ketamine. Protein determina-
tion was accomplished as described by Lowry et al.25
24. Williams, K.; Romano, C.; Molino, P. B. Mol. Pharma-
col. 1989, 36, 575.
9. Moe, S. T.; Smith, D. L.; By, K.; Egan, J. A.; Filer, C. N. J.
Labelled Compd. Radiopharm. 1998, 41, 535.
10. Mueller, A. L. IBC's New Developments in Glutamate
Pharmacology: Therapeutic Implications; San Francisco, CA,
23±24 April 1998.
25. Lowry, O. H.; Rosenbrough, N. H.; Farr, A. C.; Randall,
R. J. J. Biol. Chem. 1951, 193, 265.
26. Longa, E. Z.; Weinstein, P. R.; Carlson, S.; Cummins, R.
Stroke 1989, 20, 84.
11. Brady, E. M.; Wells, D. S.; Kierstead, A. E.; Mueller, A.
L.; Newman, M. K.; Sanguinetti, E. L.; Marriott, T. B.; Wes-
27. White, H. S.; Patel, S.; Meldrum, B. S. Epilepsy Res. 1992,
12, 217.