1172 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7
Notes
(8) deMontigny, C. Cholecystokinin Tetrapeptide Induces Panic-like
Attacks in Healthy Volunteers. Arch. Gen. Psychiatry 1989, 46,
511-517.
(9) Nichols, M. L.; Bian, D.; Ossipov, M. H.; Lai, J .; Porreca, F.
Regulation of Morphine Antiallodynic Efficacy by Cholecysto-
kinin in a Model of Neuropathic Pain in Rats. J . Pharmacol.
Exp. Ther. 1995, 275, 1339-1345.
(10) Figlewicz, D. P.; Sipolis, A. J .; Porte, D.; Woods, S. C.; Liddle,
R. A. Intraventricular CCK inhibits food intake and gastric
emptying in baboons. Am. J . Physiol. 1989, 256, R1313-R1317.
(11) Woodruff, G. N.; Hughes, J . Cholecystokinin Antagonists. Annu.
Rev. Pharmacol. Toxicol. 1991, 31, 469-501.
(12) Lin, C. W.; Holladay, M. W.; Barrett, R. W.; Wolfram, C. A. W.;
Miller, T. R.; Witte, D.; Kerwin, J . F.; Wagenaar, F.; Nadzan,
A. M. Distinct requirement for activation at CCK-A and CCK-
B/gastrin receptors: Studies with a C-terminal hydrazide ana-
logue of cholecystokinin tetrapeptide (30-33). Mol. Pharmacol.
1989, 36, 881-886.
cooled to 0 °C were added N-methylmorpholine (1.9 mL, 17
mmol) and Boc-tryptophan N-hydroxysuccinimide ester (6.15
g, 15.5 mmol). The reaction mixture was stirred for 18 h with
warming to ambient temperature. The solvent was removed
in vacuo and the residue partitioned between a solution of 10%
citric acid and ethyl acetate. The organic phase was further
washed with solutions of saturated NaHCO3 (3×) and water
(3×). After the mixture was dried over MgSO4, the solvent
was removed in vacuo. The solid residue was dissolved in ethyl
acetate-acetone and the product precipitated with the addition
of water. The product was collected and dried to yield 11.9 g
of a white solid. A mixture of the fully protected tetrapeptide
(5.0 g, 5.45 mmol) and 10% Pd/C (1.0 g) in acetic acid (100
mL) was hydrogenated for 18 h under 1 atm of hydrogen at
ambient temperature. The catalyst was filtered and the
solvent was removed in vacuo. The residue was triturated
with ether to yield 3.95 g of 4 as a light pink powder: MS
(13) Shiosaki, K.; Lin, C. W.; Kopecka, H.; Craig, R.; Wagenaar, F.;
Bianchi, B.; Miller, T.; Witte, D.; Nadzan, A. M. Development
of CCK-Tetrapeptide Analogues as Potent and Selective CCK-A
Receptor Agonists. J . Med. Chem. 1990, 33, 2950-2952.
(14) Horwell, D. C. Development of CCK-B Antagonists. Neuropep-
tides 1991, 19, 57-64.
1
(FAB+) m/e 694 (M + H)+; H NMR (DMSO-d6, 300 MHz) δ
1.11-1.62 (m, 6H), 1.32 (br s, 1H), 2.25-3.18 (m, 8H), 4.10-
4.43 (m, 4H), 6.78-7.34 (m, 12H), 7.51-7.62 (m, 2H), 8.05 (br
d, J ) 7 Hz, 1H), 8.17 (br d, J ) 7 Hz, 1H), 10.91 (br s, 1H).
Anal. Calcd for C35H47N7O8‚1.75CH3CO2H: C, 57.88; H, 6.81;
N, 12.27. Found: C, 57.84; H, 6.92; N, 12.64.
(15) Freidinger, R. M. Cholecystokinin and Gastrin Antagonists. Med.
Res. Rev. 1989, 9, 271-290.
(16) Wank, S. A.; Pisegna, J . R.; DeWeerth, A. Brain and gastrointes-
tinal cholecystokinin receptor family: Structure and functional
expression. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 8691-8695.
(17) Wank, S. A.; Pisegna, J . R.; Weerth, A. D. Cholecystokinin
receptor family: molecular cloning, structure and functional
expression in rat, guinea pig, and human. Ann. N.Y. Acad. Sci.
1994, 713, 49-66.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Ur ea -
Su bstitu ted Tetr a p ep tid es (1). Boc-Tr p -Lys(Ne-3-(m eth -
oxyp h en yla m in o)ca r bon yl)-Asp -P h e-NH2 (1e). A solution
of tetrapeptide 4 (85 mg, 0.12 mmol), phenyl isocyanate (25
µL, 0.18 mmol), and N-methylmorpholine (35 µL, 0.32 mmol)
in DMF (3 mL) was stirred at ambient temperature for 18 h.
The DMF was evaporated in vacuo and the residue directly
applied to a silica gel column and eluted with ethyl acetate-
pyridine-acetic acid-water (300:20:6:11). After evaporation
of solvents, the residue was dissolved in water-acetone (10:
1, v:v), lyophilized, and further dried (50 °C) to yield 1e (29
(18) Lee, Y.-M.; Beinborn, M.; McBride, E. W.; Lu, M.; Kolakowski,
L. F.; Kopin, A. S. The Human Brain Cholecystokinin-B/Gastrin
Receptor. J . Biol. Chem. 1993, 268, 8164-8169.
(19) Shiosaki, K.; Lin, C. W.; Kopecka, H.; Tufano, M. D.; Bianchi,
B. R.; Miller, T. R.; Witte, D. G.; Nadzan, A. M. Boc-CCK-4
Derivatives Containing Side-Chain Ureas as Potent and Selec-
tive CCK-A Receptor Agonists. J . Med. Chem. 1991, 34, 2837-
2842.
(20) Lin, C. W.; Shiosaki, K.; Miller, T. R.; Witte, D. G.; Bianchi, B.
R.; Wolfram, C. A. W.; Kopecka, H.; Craig, R.; Wagenaar, F.;
Nadzan, A. M. Characterization of Two Novel Cholecystokinin
Tetrapeptide (30-33) Analogues, A-71623 and A-70874, that
Exhibit High Potency and Selectivity for Cholecystokinin-A
Receptors. Mol. Pharmacol. 1991, 39, 346-351.
(21) Lin, C. W.; Bianchi, B. R.; Grant, D.; Miller, T.; Danaher, E. A.;
Tufano, M. D.; Kopecka, H.; Nadzan, A. M. Cholecystokinin
Receptors: Relationships among Phosphoinositide Breakdown,
Amylase Release and Receptor Affinity in Pancreas. J . Phar-
macol. Exp. Ther. 1986, 236, 729-734.
(22) Aquino, C. J .; Duncan, D. R.; Armour, R.; Berman, J . M.;
Birkemo, L. S.; Carr, R. A. E.; Croom, D. K.; Dezube, M.;
Dougherty, R. W., J r.; Ervin, G. N.; Grizzle, M. K.; Head, J . E.;
Hirst, G. C.; J ames, M. K.; J ohnson, M. F.; Miller, L. J .; Queen,
K. L.; Rimele, T. J .; Smith, D. N.; Sugg, E. E. Discovery of 1,5-
Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Re-
ceptor Agonist Activity. 1. Optimization of the Agonist “Trigger”.
J . Med. Chem. 1996, 39, 562-569.
1
mg, 39%) as a white solid: MS (FAB+) m/e 843 (M + H)+; H
NMR (DMSO-d6, 300 MHz) δ 1.05-1.68 (m, 4H), 1.30 (br s,
9H), 2.32-3.18 (m, 10H), 3.68 (s, 3H), 4.11-4.51 (m, 4H), 6.41
(d, J ) 7 Hz, 1H), 6.81 (d, J ) 7 Hz, 2H), 6.84-7.28 (m, 16H),
7.56 (br d, J ) 7 Hz, 1H), 7.89 (d, J ) 7 Hz,1H), 8.00 (m, 1H),
8.16 (m, 1H), 10.82 (br s, 1H).
Refer en ces
(1) Morley, J . E. The ascent of cholecystokinin (CCK) - from gut to
brain. Life Sci. 1982, 30, 479-493.
(2) Williams, J . A. Cholecystokinin: A hormone and a neurotrans-
mitter. Biomed. Res. 1982, 3, 107-121.
(3) Lindefors, N.; Linden, A.; Brene, S.; Sedvall, G. Persson, H. CCK
Peptides and mRNA in the Human Brain. Prog. Neurobiol. 1993,
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(4) Altar, C. A.; Boyar, W. C. Brain CCK-B receptors mediate the
suppression of dopamine release by cholecystokinin. Brain Res.
1989, 483, 321-326.
(5) Schalling, M.; Friberg, K.; Seroogy, K.; Riederer, P.; Bird, E.;
Schiffmann, S. N.; Mailleux, P.; Vanderhaeghen, J . J .; Kuga,
S.; Goldstein, M.; Kitahama, K.; Luppi, P. H.; J ouvet, M.;
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cells in the ventral mesenchephalon of several species and in
humans with schizophrenia. Proc. Natl. Acad. Sci. U.S.A. 1990,
87, 8427-8431.
(23) Boden, P. R.; Higginbottom, M.; Hill, D. R.; Horwell, D. C.;
Hughes, J .; Rees, D. C.; Roberts, E.; Singh, L.; Suman-Chauhan,
N.; Woodruff, G. N. Cholecystokinin Dipeptoid Antagonists:
Design, Synthesis, and Anxiolytic Profile of Some Novel CCK-A
and CCK-B Selective and "Mixed" CCK-A/CCK-B Antagonists.
J . Med. Chem. 1993, 36, 552-565.
(6) Geracioti, T. D. J .; Liddle, R. A. Impaired Cholecystokinin
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(24) Gonzalez-Muniz, R.; Bergeron, F.; Marseigne, I.; Durieux, C.;
and Derivatives: A New
Roques, B. P. Boc-Trp-Orn(Z)-Asp-NH2
(7) Boyce, S.; Rupniak, N. M. J .; Steventon, M.; Iversen, S. D. CCK-
8S inhibits L-dopa-induced dyskinesias in parkinsonian squirrel
monkeys. Neurology 1990, 40, 717-718.
Family of CCK Antagonists. J . Med. Chem. 1990, 33, 3199-3204.
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