STRUCTURE - ANTIGASTRIN ACTIVITY RELATIONSHIPS OF NEW SPIROGLUMIDE AMIDO ACID-DERIVATIVES

A series of new spiroglumide amido acid derivatives was synthesized an d evaluated for their ability to inhibit the binding of cholecystokini n (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. Appro priate chemical manipulations of the structure of spiroglumide (CR 219 4), i.e., mido)-5-(8-azaspiro[4,5]decan-8-yl)-5-oxopentanoic acid, led to potent and selective antagonists of CCKB/gastrin receptors. Struct ure-activity relationships are discussed. Some of these new derivative s, as, for example, compound 54 (CR 2622), i.e., '-[(3,5-dichlorobenzo yl)amino]-5'-(8-azaspiro[4.5] l)-5'-oxo-pentanonyl]amino]-5-(1-naphthy lamino)-5- oxopentanoic acid, exhibit activity 70-170 times greater th an that of spiroglumide, depending upon the model used (IC50 = 2 x 10( -8) vs 140 x 10(-8) mol in binding inhibition of [H-3]-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 ce lls of rabbit, respectively). Computer-assisted conformational analysi s studies were carried out in order to compare the chemical structure of both the agonist (pentagastrin) and the antagonist (54).