title: Synthesis and biological activity of novel, potent and long-acting analogs of AC-CCK-7 with high affinity for peripheral (type A) receptors.
abstract: 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.
authors.affiliation: Peptide Research Department, Hoffmann-La Roche, Nutley, NJ 07110.
authors.forename: W
authors.initials: W
authors.lastname: Danho
authors.forename: R C
authors.initials: RC
authors.lastname: Makofske
authors.forename: J
authors.initials: J
authors.lastname: Swistok
authors.forename: J
authors.initials: J
authors.lastname: Michalewsky
authors.forename: T
authors.initials: T
authors.lastname: Gabriel
authors.forename: N
authors.initials: N
authors.lastname: Marks
authors.forename: M J
authors.initials: MJ
authors.lastname: Berg
authors.forename: L
authors.initials: L
authors.lastname: Baird
authors.forename: V
authors.initials: V
authors.lastname: Geiler
authors.forename: G
authors.initials: G
authors.lastname: Mackie
mesh_terms: 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
chemical_list: D003692:Delayed-Action Preparations; D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; D013431:Sulfates; C074707:Ro 23-7014; D002766:Cholecystokinin