Structure activity studies of tryptophan30 modified analogs of Ac-CCK-7.
Cholecystokinin represents a family of gut hormones which among other activities, have been proposed to participate in satiety signaling. Ac-CCK-7[Ac-Tyr(SO3H)-Met-Gly-Trp30-Met-Asp-Phe-NH2 (2)] possesses the full spectrum of activity and potency of the intact hormone; thus analogs of 2 may be useful as anorectic agents. A series of derivatives has been prepared in which the tryptophan indole moiety of 2 has been modified. The new compounds were assayed in CCK binding assays using homogenated rat pancreatic membranes and bovine striatum as a source of CCK-A and CCK-B receptors respectively and in vivo in rats for anorectic activity. Although previous studies have concluded that the indole ring of Trp30 is a critical pharmacophore for the interaction of CCK with both its A and B type receptors, we find 2-Nal30-Ac-CCK-7 (20) to be nearly equipotent to 2 in both CCK binding and as an anorectic agent sensitive to blockade by the Merck CCK-A receptor antagonist MK-329. The extreme structural sensitivity of this anorectic activity is illustrated by the 1-naphthylalanine30 (19) and (benzo[b]thien-2-yl)alanine30 (21) analogs which are 30 and 100 times less potent than 2 respectively. Other mono- and bicyclic Trp30 replacements, including substituted phenylalanines, 3-quinolinylalanine, and 2-(5,6,7,8-tetrahydro)naphthylalanine, gave inactive compounds.
Danho
W
W
Roche Research Center, Hoffmann LaRoche Inc, Nutley, NJ.
Tilley
J W
JW
Shiuey
S J
SJ
Kulesha
I
I
Swistok
J
J
Makofske
R
R
Michalewsky
J
J
Wagner
R
R
Triscari
J
J
Nelson
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry; D001798:Blood Proteins / Q000737:chemistry; D002417:Cattle; D003342:Corpus Striatum / Q000737:chemistry; D008969:Molecular Sequence Data; D010179:Pancreas / Q000737:chemistry; D010446:Peptide Fragments / Q000032:analysis / Q000737:chemistry*; D051381:Rats; D012844:Sincalide / Q000032:analysis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry*
D001067:Appetite Depressants; D001798:Blood Proteins; D010446:Peptide Fragments; C028035:stable plasma protein solution; C025997:cholecystokinin (27-33); D014364:Tryptophan; D012844:Sincalide