PubMed · 7156438
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
F Larraín, O Danús. [Digestive hormones].. https://pubmed.ncbi.nlm.nih.gov/7156438/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
The lipophilicity of 17 newly synthesized potential NMDA and cholecystokinin antagonist 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acid derivatives has been investigated. The apparent partition coefficients of two amphoteric compounds of overlapping protonation (Q1 and Q2) were determined by shake-flask method and converted into true log P values using the protonation microconstants. The difference between their lipophilicity expressed with the true partition coefficients was less, than it could be expected from the 2D structures and was explained with conformational preferences and formation of intramolecular interactions. Out of the other 15 monoprotic quinazolone compounds the lipophilicity of ten molecules (Q8-Q17, experimental set) was determined by TLC method with the help of a calibration set consisting of 12 standard molecules, five quinazolones (Q3-Q7) and seven pyrido[1,2-a]pyrimidines (PP1-PP7). In order to justify the suitability of pyrido-pyrimidines as standards for the chromatographic log P determination of quinazolones, first Q3-Q7 were examined by TLC and HPLC using PP1-PP7 for calibration. Data showed good agreement of results obtained by shake-flask and two different chromatographic methods indicating the similar chromatographic behavior of the two bicyclic systems and the relevance of PP1-PP7 to extend the calibration set of quinazolones. The obtained log P values proved mostly the expected structure-activity relationships. Some findings, however, have revealed specific partition behavior of the compounds providing useful information in the estimation of their pharmacokinetics, and these are discussed in the paper.
The protonation macroconstants (log K) of 4(3H)-quinazolone (1) and two 2-methyl-4-oxo-3H-alkyl-quinazoline-3-carboxylic acid derivatives (2,3) were determined by pH-potentiometry. The acid-base chemistry of compounds 2 and 3, where proton-bindings take place in an overlapping fashion, was described in terms of protonation microconstants as well. Microspeciation was carried out by two means: UV-pH titration (selective, pH-dependent monitoring of the N1-binding site), and deductively (using a derivative compound as covalently fixed model of one of the protonation isomers). The microconstant values obtained by the two different methods are in agreement within 0.05 log K units. Microspeciation revealed remarkable differences between the two homologue compounds (2 and 3). The microconstant values show that insertion of a second methylene moiety into the aliphatic acid side-chain (1) increases the electron-density and most basicity parameters of both functional groups; (2) significantly modifies the extent of site-site interactions in the molecule; (3) opens new conformational preferences by N1 ring nitrogen-carboxylic group intramolecular hydrogen bond formation and (4) reverses the predominantly zwitterion-involved protonation pathway into a neutral form-involved pathway. These molecules exemplify that microconstant values allow the comparative prediction and quantitative evaluation of pharmacokinetic behaviour, and signify the fact that microspeciation is a powerful tool in the process of drug development.
Cholecystokinin (CCK), a peptide synthesized in the small bowel, is secreted into the blood stream after food intake. Its effects are primarily hormonal but of equal significance is that of a neurotransmitter. Its central role as a digestive peptide is illustrated by the following sequence: Mostly fat and protein of a consumed meal liberate CCK which triggers the contraction of the gallbladder and stimulates secretion of pancreatic enzymes. At the same time CCK slows down gastric emptying leading to an optimal ratio of foodstuff and digestive secreta. Via activation of afferent nerves CCK induces the sensation of saturation and thus limits food intake. Many questions remain open or undefined in this context but two conclusions may be drawn. 1. The significance of Pawlowian neural regulation of digestive functions is supported by new evidence, although hormones may support or modulate these functions. 2. It has become clear that a peptide may assume diverse regulatory functions be it as a hormone or as a neurotransmitter. Dear old concepts have therefore to be revised.