Tetrapeptide CCK-A agonists: effect of backbone N-methylations on in vitro and in vivo CCK activity.
N-Methylation of backbone amide bonds was conducted on a tetrapeptide that had been identified previously (Shiosaki, K.; et al. J. Med. Chem. 1991, 34, 2387-2842) as a potent and selective CCK-A agonist. N alpha-Methylation at the position corresponding to Asp32 (CCK-33 numbering) was consistent with high affinity, efficacy, and selectivity for the CCK-A receptor. Combination of this (N-Me)Asp with the (N-Me)Phe modification also provided a highly active analogue. The observation of parallel structure-binding affinity profiles with respect to sites of N-methylation in the C-terminal regions of tetrapeptide vs heptapeptide CCK analogues suggests that the two series interact similarly with the CCK-A receptor.
Holladay
M W
MW
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Kopecka
H
H
Miller
T R
TR
Bednarz
L
L
Nikkel
A L
AL
Bianchi
B R
BR
Witte
D G
DG
Shiosaki
K
K
Lin
C W
CW
Asin
K E
KE
D000595:Amino Acid Sequence; D000818:Animals; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000737:chemistry; D004435:Eating / Q000187:drug effects; D008745:Methylation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000378:metabolism
D009842:Oligopeptides; D011949:Receptors, Cholecystokinin; D013431:Sulfates; D002766:Cholecystokinin