title: Structure-antigastrin activity relationships of new spiroglumide amido acid derivatives.
abstract: A series of new spiroglumide amido acid derivatives was synthesized and evaluated for their ability to inhibit the binding of cholecystokinin (CCK) to guinea pig brain cortex (CCKB receptors) and peripheral rat pancreatic acini (CCKA receptors), as well as to inhibit in vitro the gastrin-induced Ca2+ increase in rabbit gastric parietal cells. Appropriate chemical manipulations of the structure of spiroglumide (CR 2194), i.e., (R)-4-(3,5-dichlorobenzamido)-5-(8-azaspiro[4.5]decan- 8-yl)-5-oxopentanoic acid, led to potent and selective antagonists of CCKB/gastrin receptors. Structure-activity relationships are discussed. Some of these new derivatives, as, for example, compound 54 (CR 2622), i.e., (S)-4-[[(R)-4'-[(3,5-dichlorobenzoyl)-amino]-5'-(8- azaspiro[4.5]decan-8-yl)-5'-oxo-pentanoyl]amino]-5- (1-naphthylamino)-5-oxopentanoic acid, exhibit activity 70-170 times greater than that of spiroglumide, depending upon the model used (IC50 = 2 x 10(-8) vs 140 x 10(-8) mol in binding inhibition of [3H]-N-Me-N-Leu-CCK-8 in guinea pig brain cortex and IC50 = 0.7 x 10(-8) vs 122.3 x 10(-8) mol in inhibition of gastrin-induced Ca2+ mobilization in parietal cells of rabbit, respectively). Computer-assisted conformational analysis studies were carried out in order to compare the chemical structure of both the agonist (pentagastrin) and the antagonist (54).
authors.affiliation: Rotta Research Laboratorium, Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Makovec
authors.forename: W
authors.initials: W
authors.lastname: Peris
authors.forename: S
authors.initials: S
authors.lastname: Frigerio
authors.forename: R
authors.initials: R
authors.lastname: Giovanetti
authors.forename: O
authors.initials: O
authors.lastname: Letari
authors.forename: L
authors.initials: L
authors.lastname: Mennuni
authors.forename: L
authors.initials: L
authors.lastname: Revel
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017076:Computer-Aided Design; D015195:Drug Design; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000494:pharmacology; D005973:Glutamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D008968:Molecular Conformation; D015394:Molecular Structure; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010418:Pentagastrin / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000897:Anti-Ulcer Agents; D005755:Gastrins; D010880:Piperidines; D011949:Receptors, Cholecystokinin; D013141:Spiro Compounds; D005973:Glutamine; D002766:Cholecystokinin; D010418:Pentagastrin