3-(1H-indazol-3-ylmethyl)-1,5-benzo-diazepines: CCK-A agonists that demonstrate oral activity as satiety agents

Full text of DOI:10.1021/jm960249k

J . Med. Chem. 1996, 39, 2655-2658
Communications to the Editor
Sch em e 1a
2655
3-(1H-In d a zol-3-ylm eth yl)-1,5-ben zo-
d ia zep in es: CCK-A Agon ists Th a t
Dem on str a te Or a l Activity a s Sa tiety
Agen ts
Brad R. Henke,*,† Timothy M. Willson,†
Elizabeth E. Sugg,† Dallas K. Croom,‡,§
Robert W. Dougherty, J r.,§, Kennedy L. Queen,
Larry S. Birkemo,‡ Gregory N. Ervin,‡,|
Mary K. Grizzle,‡ Michael F. J ohnson,‡ and
Michael K. J ames‡,§
Glaxo Wellcome Research and Development, Five Moore
Drive, Research Triangle Park, North Carolina 27709
Received March 29, 1996
We recently reported the identification of a series of
3-(phenylureido)-1,5-benzodiazepine CCK-A agonists.1
These compounds were the first reported nonpeptidyl
CCK-A agonists. Unfortunately, they lacked binding
selectivity for CCK-A vs CCK-B receptors and were not
orally active as satiety agents in rodent feeding models.
Subsequent systematic modification of the C-3 ureido
substituent in this series led to the development of a
CCK-A binding-selective partial agonist 1 (Figure 1).2
While amide 1 showed CCK-A agonist activity in a
mouse gallbladder-emptying assay following oral dosing,
it was also not orally active in a rat feeding model.
Reasoning that the partial agonist activity of 1 may be
connected to its inability to inhibit feeding, studies were
initiated to identify binding-selective CCK-A full ago-
nists. This paper reports the biological profile of a series
of isosteric replacements for the C-3 phenyl amide
moiety.
Ch em istr y. Compounds 2-10 were synthesized
using 1,5-benzodiazepine 11 (R ) H or OCH3) as a key
intermediate (Scheme 1). Alkylation of N-phenyl-1,2-
phenylenediamine with the appropriate bromoaceta-
mide followed by condensation with malonyl dichloride
afforded 11 in rapid fashion. The C-3 substituent was
introduced via deprotonation using KN(TMS)2 or NaN-
(TMS)2 as the base followed by addition of the requisite
alkyl halide. Deprotection, if necessary, was carried out
under standard conditions. Formation of the C-3 qua-
ternary analogs was achieved by a second deprotona-
tion/alkylation sequence with the appropriate alkyl
halide, followed by deprotection if necessary. The
various alkyl halides used in construction of 2-10 were
synthesized using established literature methods.
Resu lts a n d Discu ssion . The strategy for modifica-
tion of the C-3 pharmacophore was suggested by study-
ing the structure of the selective CCK-A antagonist
asperlicin,3 which has been used by several groups as a
a
Reagents: (i) 2-bromo-N-isopropyl-N-phenylacetamide (R1
)
)
H) or 2-bromo-N-isopropyl-N-(4-methoxy)phenylacetamide (R1
OCH3), K2CO3, DMF, 18 h; (ii) malonyl dichloride, THF, 0 °C to
room temperature, 18 h; (iii) NaN(TMS)2 or KN(TMS)2, room
temperature, DMF, 15 min; Ar-CH2-Br, DMF, room temperature,
2-5 h; (iv) KN(TMS)2, DMF, 0 °C, 15 min; MeI, DMF, room
temperature, 3 h; (v) deprotection (if necessary).
template for the development of subtype-selective CCK
antagonists.4 Pioneering work at Merck resulted in a
series of 1,4-benzodiazepine CCK-A selective antago-
nists,5,6 suggesting that the benzodiazepine substructure
provides a proper structural motif for interaction with
the CCK receptor. Researchers at both Merck5 and
Lilly4d,e also demonstrated that the 3-indolinylmethyl
group embedded within the structure of asperlicin was
an important element for bioactivity. In addition, this
moiety is structurally similar to L-tryptophan, a key
amino acid required for agonist activity in the peptide
sequence of CCK and various peptidomimetics of CCK.7
Compounds 2-10 were evaluated for in vitro func-
tional efficacy in inducing contraction of isolated guinea
pig gallbladder (Table 1).8 Compounds were tested at
30 µM concentration and their efficacy normalized to
CCK-8 at 1 µM. The contractile activity of all com-
pounds was reversed with the CCK-A selective antago-
nist MK-329.5 To investigate the viability of our
strategy in the 1,5-benzodiazepine CCK-A agonist se-
ries, the phenyl amide moiety in 1 was replaced by a
3-indolylmethyl group. This modification maintains
agonist activity, with the 3-indolyl analog 2 having
equal efficacy to that of amide 1 (Table 1). Previous
work1 had demonstrated that replacement of the p-
hydrogen in the anilide “trigger” portion of the molecule
with a methoxy group provided a modest increase in
efficacy. However, in the indole series this substitution
led to a small decrease in efficacy (2 vs 3, Table 1).
Removal of the C-3 methyl substituent provided a slight
increase in efficacy (3 vs 4). Efforts were then directed
toward replacement of the indole moiety. The 3-inda-
zole moiety was initially chosen on the basis of its
capability to function as an indole bioisostere in other
systems.9 Replacement of the indole group with a
* Address correspondence to: Brad R. Henke, Glaxo Wellcome
Research and Development, N2112, Five Moore Dr., Research Triangle
Park, NC 27709. Tel: (919) 483-1363. FAX: (919) 315-5668. E-mail:
henke∼br@glaxo.com.
† Department of Medicinal Chemistry.
‡ Department of Pharmacology.
§ Current address: Inspire Pharmaceuticals, Durham, NC 27703.
Department of Receptor Biochemistry.
| Current address: Department of Psychology, Brigham Young
University, Provo, UT 84602.
S0022-2623(96)00249-X CCC: $12.00 © 1996 American Chemical Society

2656 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Communications to the Editor
F igu r e 1.
Ta ble 1. In Vitro Activity of 1,5-Benzodiazepine CCK-A Agonists
structuresa
R2
functional assayb
binding assayc
no.
R1
X
Y
ED50 (nM)
% max
CCK-A (pIC50
)
CCK-B (pIC50
)
A/B sel
CCK-8
1
2
3
4
5
6
7
-
-
H
OCH3
OCH3
H
OCH3
OCH3
H
OCH3
OCH3
-
-
-
2 ( 1 (5)
190 ( 20 (4)
470 (1)
530 (1)
340 (1)
20 (1)
320 (1)
109 ( 60 (4)
140 (1)
100
8.88 ( 0.22 (8)
7.12 ( 0.02 (3)
6.97 ( 0.09 (3)
8.08 ( 0.24 (4)
7.96 ( 0.14 (3)
6.92 ( 0.12 (3)
7.88 ( 0.02 (3)
7.64 ( 0.12 (5)
7.06 ( 0.05 (3)
7.37 ( 0.43 (3)
6.51 ( 0.16 (5)
9.46 ( 0.04 (8)
5.08 ( 0.04 (3)
-
0.3
110
-
2090
480
20
5100
50
2
60
-
-
-
80 (4)
80 (1)
60 (3)
70 (4)
80 (2)
80 (3)
100 (6)
90 (2)
90 (3)
40 (2)
CH3
CH3
H
CH3
CH3
H
H
H
H
CH
CH
CH
N
N
N
N
N
N
NH
NH
NH
NH
NH
NH
NH
4.76 ( 0.26 (5)
5.28 ( 0.08 (3)
5.58 ( 0.05 (3)
4.16 ( 0.23 (3)
6.00 ( 0.23 (4)
6.75 ( 0.10 (3)
5.62 ( 0.20 (3)
4.00 ( 0.0 (2)
8
9
10
NCH3
NCH2Ph
70 ( 10 (2)
340 (1)
320
a
b
Figure 1. Functional activity in the isolated guinea pig gallblader following incubation with the test ligand for 30 min at 37 °C;
ED50, concentration at which 50% of the maximal contraction was observed ( SE (number of determinations); % max (number of
determinations), relative efficacy as determined by the maximal contraction observed at 30 µM standardized to CCK-8 (1 µM) ) 100%,
all values (5%. Reversal of contraction with MK-329 (1 µM) was used to verify a CCK-A receptor mediated response. c Binding affinity
for human CCK-A and CCK-B receptors; pIC50, -log of the concentration that displaced 50% of [125I]Bolton-Hunter CCK-8 from membrane
preparations isolated from CHO-K1 cells stably transfected with cDNA of human CCK-A and CCK-B receptors ( SE (number of
determinations); -, not determined; A/B sel, CCK-A receptor selectivity calculated from IC50 (B)/IC50 (A).
3-indazolyl moiety tended to provide an increase in
efficacy (3 vs 6, 4 vs 7, Table 1). Notably, indazole 7
was a full agonist, being as efficacious as CCK-8 in this
assay. In parallel to the indole series, removal of the
p-methoxy group resulted in a slight decrease in efficacy
(7 vs 8). Methylation of the indazole N-1 nitrogen
decreased efficacy slightly (7 vs 9), while N-benzyl
analog 10 had substantially reduced agonist activity.
Importantly, compounds 2-10 also displayed submi-
cromolar potencies ranging from 20 to 500 nM in the
guinea pig gallbladder assay (Table 1). Interpretations
on potency differences within this series are precluded
due to the lack of a significant number of full dose-
response experiments for most entries.
Receptor binding affinities for compounds 1-10 were
measured on membrane preparations from CHO-K1 cell
lines stably transfected with cDNA from either human
CCK-A10 or CCK-B11 receptors. IC50 values were de-
termined using competitive radioligand binding with
labeled CCK-8. Replacement of the N-phenylamide
with the 3-indazolyl moiety resulted in a 5-fold drop in
selectivity (1 vs 5, Table 1). Removal of the C-3 methyl
group resulted in a decrease in A/B selectivity in both
the indole and indazole series (3 vs 4, 6 vs 7). Previous
work1 had shown that incorporation of a p-methoxy
group in the anilide “trigger” portion of the molecule
provided a slight increase in A/B binding selectivity.
Incorporation of this moiety in the indole series led to
increased affinity for the CCK-A receptor (2 vs 3) and
provided a substantial improvement in the indazole
series (5 vs 6, 8 vs 7), with compound 6 displaying
>5000-fold selectivity for the CCK-A receptor. In
general, optimal A/B selectivity in this series is achieved
by incorporation of both a p-methoxy group in the
anilide trigger and a methyl group at C-3 of the 1,5-
benzodiazepine ring.
Indazole 7 was chosen for in vivo evaluation based
on in vitro efficacy, as it was the only compound which
demonstrated full agonist activity and moderate CCK-A
binding selectivity. Compound 7 was tested in a mouse
gallbladder-emptying assay1 to examine whether the
increased in vitro efficacy translated to increased CCK-A
agonist activity in vivo. This assay measures the extent
of CCK-mediated gallbladder emptying 30 min after
compound is administered12 and provides a direct
physiological reading of peripheral CCK-A agonist
activity. Indazole 7 was both more potent and more
efficacious than amide 1 in this assay (Table 2), showing
efficacy equal to that of CCK-8 when administered
intraperitoneally. This increase in bioactivity also held
true upon oral administration, with 7 demonstrating full
agonist activity and a substantial improvement in
potency over amide 1.
Having identified 7 as an orally active full agonist in
vivo in a mouse gallbladder emptying assay, the satiety
effects of this compound were evaluated in a rat feeding
model. The in vivo effect of 7 on feeding was assessed
in Long-Evans rats conditioned to a liquid diet and
fasted for 2 h prior to oral administration of drug. Drug
administration was followed immediately by a saline
oral preload. Food access was provided 20 min later,
and food intake was measured at 30, 90, and 180 min.
d-Amphetamine was used as a positive control. This
model provides measurement of the anorectic activity

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2657
Ta ble 2. In Vivo Activity of 1,5-Benzodiazepine CCK-A
Agonists 1 and 7
Subsequent structure-activity studies have identified
indazole 7 as a binding-selective CCK-A full agonist
which is orally active in a mouse gallbladder emptying
assay. In addition, compound 7 is the first CCK-A
agonist which has demonstrated suppression of food
intake when given orally in a rat feeding model. This
compound, GW 5823, shows promise as an orally active
satiety agent which may be useful for the treatment of
obesity.
mouse gallbladder emptyinga
ip
po
no.
ED50 (nmol/kg) % emptyb ED50 (nmol/kg) % emptyb
CCK-8
1
7
0.03
30
0.2
95
70
90
-
-
70
90
1000
8.0
a
Following overnight food deprivation, male CD-1 mice (10
animals per dose) were treated (ip or po) with vehicle (ethanol/
propylene glycol/water, 2:3:5, 1 mL/kg) or test compound dissolved
in vehicle (1 mL/kg). Animals were sacrificed (CO2) 30 min after
drug treatment, and the gallbladders were removed and weighed.
Gallbladder wet weights of the treated animals were normalized
Ack n ow led gm en t. We gratefully acknowledge Dr.
Laurence J . Miller (Mayo Clinic, Rochester, MN) for
providing the CHO-K1 cells stably transfected with
human CCK-A and CCK-B receptors. B.R.H. acknowl-
edges Dr. Rayomand Unwalla for many helpful discus-
sions.
b
to the vehicle control group; -, not determined. % empty )
percent emptying, p < 0.05 at 0.1 µmol/kg (ip) or 10 µmol/kg (po)
relative to CCK-8 at 1 nmol/kg, ip.
Su p p or tin g In for m a tion Ava ila ble: Experimental, spec-
tral, and analytical data for compound 7 (4 pages). Ordering
information is given on any current masthead page.
Refer en ces
(1) Aquino, C. J .; Armour, D. R.; Berman, J . M.; Birkemo, L. S.;
Carr, R. A. E.; Croom, D. K.; Dezube, M.; Dougherty, R. W.;
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) Receptor Agonist Activity.
I. Optimization of the Agonist “Trigger”. J . Med. Chem. 1996,
39, 562-569.
(2) Willson, T. M.; Henke, B. R.; Momtahen, T. M.; Myers, P. L.;
Sugg, E. E.; Unwalla, R. J .; Croom, D. K.; Dougherty, R. W.;
Queen, K. L.; J ames, M. K. 3-[2-(N-Phenylacetamide)]-
1,5-benzodiazepines: Orally Active, Binding Selective CCK-A
Agonists. J . Med. Chem., in press.
F igu r e 2. Key: (b) vehicle; (0) 7, 0.1 µmol/kg; (]) 7, 1.0 µmol/
kg; (2) 7, 10 µmol/kg; (O) d-Amphetamine, 2 mg/kg. Male
Long-Evans rats (225-300 g) were conditioned for 2 weeks
to consume a palatable liquid diet (Bio-Serve F1657, French-
town, NJ ) after a 2 h fast. On pretreatment day, rats were
fasted (100 min) and injected po with drug vehicle (propylene
glycol, PG, 1 mL/kg) and an oral preload of saline (0.9% NaCl,
8 mL/kg). Liquid diet access was provided 20 min later, and
consumption was measured at 30, 90, and 180 min. To qualify
for the drug treatment study, rats had to consume at least 8
mL of liquid diet within the first 30 min on the pretreatment
day. The next day, following the 100 min deprivation, rats (8-
10 animals/dose) were treated po with vehicle (PG, 1 mL/kg)
or various doses (0.1-10 µmol/kg) of test compound dissolved
in PG (1 mL/kg), immediately followed by the saline oral
preload. Food access was again provided 20 min later, and food
intake was measured at 30, 90, and 180 min. All food intake
data were normalized for each rat to the respective values from
the pretreatment day. *p < 0.05 using Dunnett’s multiple
comparison test.
(3) Chang, R. S.; Lotti, V. J .; Monaghan, R. L.; Birnbaum, J .;
Stapley, E. O.; Goetz, M. A.; Albers-Schonberg, G.; Patchett, A.
A.; Liesch, J . M.; Hensens, O. D. A Potent Nonpeptide Chole-
cystokinin Antagonist Selective for Peripheral Tissues Isolated
from Aspergillus Alliaceus. Science 1985, 230, 177-179.
(4) (a) Evans, B. E.; Bock, M. G. Promiscuity in Receptor Ligand
Research: Benzodiazepine-based Cholecystokinin Antagonists.
Adv. Med. Chem. 1993, 2, 111-52. (b) Evans, B. E.; Rittle, K.
E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W.
L.; Gould, N. P.; Lundell, G. F.; Homnick, C. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J .; Cerino, D. J .; Chen,
T. B.; King, P. J .; Kunkel, K. A.; Springer, J . P.; Hirshfield, J .
Design of Nonpeptidal Ligands for a Peptide Receptor: Chole-
cystokinin Antagonists. J . Med. Chem. 1987, 30, 1229-1239. (c)
Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J .; Cerino, D. J .; Chen,
T. B.; King, P. J .; Kunkel, K. A.; Springer, J . P.; Hirshfield, J .
Methods for Drug Discovery: Development of Potent, Selective,
Orally Effective Cholecystokinin Antagonists. J . Med. Chem.
1988, 31, 2235-2246. (d) Yu, M. J .; Thrasher, K. J .; McCowan,
J . R.; Mason, N. R.; Mendelsohn, L. G. Quinazoline Cholecys-
tokinin-B Receptor Ligands. J . Med. Chem. 1991, 34, 1505-
1508. (e) Yu, M. J .; McCowan, J . R.; Mason, N. R.; Deeter, J . B.;
Mendelsohn, L. G. Synthesis and X-ray Crystallographic Analy-
sis of Quinazoline Cholecystokinin/Gastrin Receptor Ligands. J .
Med. Chem. 1992, 35, 2534-2542.
(5) Evans, B. E.; Bock, M. G.; Rittle, K. E.; Dipardo, R. M.; Whitter,
W. L.; Veber, D. L.; Anderson, P. S.; Freidinger, R. M. Design of
Potent, Orally Effective, Nonpeptidyl Antagonists of the Peptide
Hormone Cholecystokinin. Proc. Natl. Acad. Sci. U.S.A. 1986,
83, 4918-4922.
(6) Bock, M. G.; Dipardo, R. M.; Evans, B. E.; Rittle, K. E.; Whitter,
W. L.; Veber, D. F.; Anderson, P. S.; Freidinger, R. M. Benzo-
diazepine Gastrin and Brain CCK Receptor Ligands: L365,260.
J . Med. Chem. 1989, 32, 13-16.
(7) (a) Hermkens, P. H. H.; Ottenheijm, H. C. J .; van der Werf-
Pieters, J . M. L.; Broekkamp, C. L. E.; de Boer, T.; van Nispen,
J . W. CCK-A Agonists: Endeavours Involving Structure-Activity
Relationship Studies Recl. Trav. Chim. Pays-Bas 1993, 112, 95-
106. (b) Shiosaki, K.; Lin, C. W.; Kopecka, H.; Craig, R.;
Wagenaar, F. L.; 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. (c) 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 Selective CCK-A Receptor Agonists. J . Med. Chem. 1991,
of CCK-A agonists, taking into account both vagally-
mediated behavioral satiety effects in combination with
effects through inhibition of gastric emptying.13 The
results (Figure 2) demonstrate indazole 7 was effective
at reducing food intake to 40% of vehicle controls when
given orally at a dose of 10 µmol/kg, with statistically
significant reduction in food intake occurring at a dose
of 1 µmol/kg after 180 min. At the higher dose an effect
on food intake could be seen up to 24 h after dosing (data
not shown). The chronic effectiveness of compound 7
in this model has not been evaluated.
Con clu sion . Previous work1,2 has identified 1,5-
benzodiazepine CCK-A agonists whose efficacy and
binding selectivity are dependent on the structure of the
C-3 pharmacophore. This report illustrates that re-
placement of the C-3 urea or amide pharmacophore with
a 3-indolylmethyl group maintains agonist activity.

2658 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Communications to the Editor
34, 2837-2842. (d) Dezube, M.; Sugg, E. E.; Birkemo, L. S.;
Croom, D. K.; Dougherty, R. W., J r.; Ervin, G. N.; Grizzle, M.
K.; J ames, M. K.; J ohnson, M. F.; Mosher, J . T.; Queen, K. L.;
Rimele, T. J .; Sauls, H. R.; Triantafillou, J . A. Modification of
Receptor Selectivity and Functional Activity in Cholecystokinin
Peptoid Ligands. J . Med. Chem. 1995, 38, 3384-3390.
(11) (a) Pisegna, J . R.; de Weerth, A.; Huppi, K.; Wank, S. A.
Molecular Cloning of the Human Brain and Gastric Cholecys-
tokinin Receptor: Structure, Functional Expression and Chro-
masomal Localization. Biochem. Biophys. Res. Commun. 1992,
189 , 296-303. (b) Lee, Y. M.; Beinborn, M.; McBride, E. W.;
Lu, M.; Kolakowski, L. F., J r.; Kopin, A. S. The Human Brain
Cholecystokinin-B/Gastrin Receptor. Cloning and Characteriza-
tion. J . Biol. Chem. 1993, 268, 8164-8169.
(12) Makovec, F.; Bani, M.; Cereda, R.; Chiste, R.; Pacini, M. A.;
Revel, L.; Rovati, L. C. Antispasmodic Activity on the Gallblad-
der of the Mouse of CR 1409 (Lorglumide), a Potent Antagonist
of Peripheral CCK. Pharmacol. Res. Commun. 1987, 19, 41-
51.
(13) For the effects of CCK on rat feeding behavior by peripheral and
centrally mediated pathways and gastric emptying, see: (a)
Della-Fera, M. A.; Coleman, B. D.; Baile, C. A. CNS injection of
CCK in rats: Effects on Real and Sham Feeding and Gastric
Emptying. Am. J . Physiol. 1990, 258, R1165-R1169. (b) Craw-
ley, J . Clarification of the Behavioral Functions of Peripheral
and Central Cholecystokinin: Two Separate Peptide Pools.
Peptides 1985, 6, 129-36. (c) Moran, T. H.; McHugh, P. R.
Cholecystokinin Suppresses Food Intake by Inhibiting Gastric
Emptying. Am. J . Physiol. 1982, 242, R491-R497.
(8) Sugg, E. E.; Kimery, M. J .; Ding, J . M.; Kenakin, D. C.; Miller,
L. J .; Queen K. L.; Rimele, T. J . CCK-A Receptor Selective
Antagonists Derived from the CCK-A Receptor Selective Tet-
rapeptide Agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (A-71623).
J . Med. Chem. 1995, 38, 207-211.
(9) Fludzinski, P.; Evrard, D. A.; Bloomquist, W. E.; Lacefield, W.
B.; Pfeifer ,W.; J ones, N. D.; Deeter, J . B.; Cohen, M. L. Indazoles
as Indole Bioisosteres: Synthesis and Evaluation of the Tropanyl
Ester and Amide of Indazole-3-carboxylate as Antagonists at the
Serotonin 5HT3 Receptor. J . Med. Chem. 1987, 30, 1535-1537.
(10) (a) Ulrich, C. D.; Ferber, I.; Holicky, E.; Hadac, E.; Buell, G.;
Miller, L. J . Molecular Cloning and Functional Expression of
the Human Gallbladder Cholecystokinin A Receptor. Biochem.
Biophys. Res. Commun. 1993, 193, 204-211. (b) de Weerth, A.;
Pisegna, J . R.; Huppi, K.; Wank, S. A. Molecular Cloning,
Functional Expression and Chromasomal Localization of the
Human Cholecystokinin Type A Receptor. Biochem. Biophys.
Res.
Commun.
1993,
194,
811-818.
J M960249K