Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger".
Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.
Aquino
C J
CJ
Department of Medicinal Chemistry, Glaxo Wellcome, Research Triangle Park, North Carolina 27709, USA.
Armour
D R
DR
Berman
J M
JM
Birkemo
L S
LS
Carr
R A
RA
Croom
D K
DK
Dezube
M
M
Dougherty
R W
RW
Ervin
G N
GN
Grizzle
M K
MK
Head
J E
JE
Hirst
G C
GC
James
M K
MK
Johnson
M F
MF
Miller
L J
LJ
Queen
K L
KL
Rimele
T J
TJ
Smith
D N
DN
Sugg
E E
EE
D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D001067:Appetite Depressants; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines