Synthesis and biological activity of novel, potent and long-acting analogs of AC-CCK-7 with high affinity for peripheral (type A) receptors.
Analogs of cholecystokinin (CCK-7) in which the N-terminal Tyr(SO3H) was acetylated, Asp6 replaced with Thr(SO3H) and Phe7 replaced with N-methyl-Phe were prepared by solid-phase peptide synthesis and evaluated for their receptor-binding activity and ability to suppress appetite. The receptor binding activities of these synthetic analogs of CCK-7 and their selectivity for the CCK-A and CCK-B receptor subtypes were determined using solubilized membrane preparations from rat pancreatic tissue and bovine striatum. The synthetic peptide Ac-Tyr(SO3H)-Met-Gly-Trp-Met-Thr(SO3H)-N-methyl-Phe-NH2 (referred to as Ro 23-7014) demonstrated superior satiating potency (ED50 = 0.3 micrograms/kg, i.p.), increased selectivity for CCK-A receptors (400-fold), increased resistance to peptidergic degradation and a longer duration of action (4 to 5 hours). This analog also effectively suppressed food intake following intranasal administration (ED50 = 100 micrograms/kg). These studies demonstrate the feasibility of designing analogs of CCK-8 with greater selectivity, potency and duration of action, which may be useful as nonsystemically administered appetite suppressants.
Danho
W
W
Peptide Research Department, Hoffmann-La Roche, Nutley, NJ 07110.
Makofske
R C
RC
Swistok
J
J
Michalewsky
J
J
Gabriel
T
T
Marks
N
N
Berg
M J
MJ
Baird
L
L
Geiler
V
V
Mackie
G
G
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D003692:Delayed-Action Preparations; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D013431:Sulfates
D003692:Delayed-Action Preparations; D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; D013431:Sulfates; C074707:Ro 23-7014; D002766:Cholecystokinin