Molecular shape analysis for quantitative drug design

One of the goals of the rational drug design using quantitative structure-activity relationship [QSAR]' is to derive a relationship between some numerical expression of the structures of compounds and their activity. The objective is to predict the structure[s] of more active compounds. The pioneering work of Hansch el at. provided a formula for deriving QSARs, which could be used to predict activity from structure. A major limitation of this approach is that its descriptors are derived from 2-dimensional structures. Comparative molecular field analysis, CoMFA, molecular shape analysis, MSA, distance geometry, and molecular matrices are four methods which explicitly treat the 3-dimensional structure of the ligand and thus yield 3-dimensional quantitative structure-activity relationships, 3D-QSARs. The present article will review the molecular shape analysis MSA, as one of the most valuable 3D-QSAR method. MSA seeks the active conformation of a molecule, expresses molecular shape similarity in terms of a variety of scalar descriptors, such as common overlap steric volume Vo [COSV], measured relative to some reference compound and conformation, and permits the use of other common 2- and 3-dimensional descriptors in the development of structure-activity models

Synthesis and biological activities of some human gastrin analogs

The synthesis of analogs of the C-terminal tridecapeptide of gastrin in described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethytalcohol or with 2-phenylethylamine, or by replacing the peptid bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38 [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-((CH2NH)-Leu11]-HG-13-I 31 and (Trp10-((CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-((CH2NH)-Asp12]-HG-13-I 30 and [Leu11-((CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.

Secretory response of cultured acinar cells of rat pancreas to cholecystokinin

To determine the adequate models for studying the functions of pancreatic acinar cells, secretory responses to CCK and to CCK receptor antagonist, L-364, 718 were examined in freshly isolated cells and confluent monolayer cells. The results showed that as CCK concentration increased, releases of amylase and lipase increased dose-dependently reaching a maximum at 10(-9) M in acinar cells cultured in serum-containing media as well as in serum-free media. Acinar response to CCK was partially inhibited by L-364, 718, L-364, 718 itself had no effect on the releases of both amylase and lipase. Confluent monolayer of acinar cells released relatively low levels of enzymes and exhibited less response to CCK. In conclusion, short-term culture of acinar cells would be suitable to study the regulation of pancreatic enzyme secretion, and serum factors do not influence acina response to the secretagogues. However, confluency of the acinar cells resulted in the loss of their secretory potential in the aspect of amylase and lipase release.

A quantitative structure-activity relationship study of ligands exhibiting agonist and antagonist actions with cholecystokinin-receptors.

Observed biological activities of substituted phenyl urea/thiourea tetrapeptides as agonists with the cholecystokinin-alimentary canal (CCK-A) receptor, and (R)-4-benzamido-5-oxopentanoic acid derivatives with both peripheral (CCK-A) and the central (CCK-B) (brain) receptors have been shown to be correlated with various physicochemical, e.g. pi, sigma, and structural, e.g. Vw and dummy, I, parameters. These results were, then interpreted to predict promising criteria for having ligands with better affinity with the CCK receptors.