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 l‐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.