ABSTRACT
(1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.
Subject(s)
Cetirizine/chemistry , Cetirizine/pharmacokinetics , Histamine H1 Antagonists/chemistry , Histamine H1 Antagonists/pharmacokinetics , Acids/chemistry , Algorithms , Alkalies/chemistry , Cetirizine/chemical synthesis , Histamine H1 Antagonists/chemical synthesis , Hydrogen-Ion Concentration , Hydroxyzine/chemistry , Hydroxyzine/pharmacokinetics , Indicators and Reagents , Magnetic Resonance Spectroscopy , Piperazines/chemistry , ProtonsABSTRACT
A series of compounds containing privileged scaffolds of the known histamine H(1) receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D(3) receptor. A pharmacological screening was carried out at dopamine D(2) and D(3) receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D(3)receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD(3)K(i)=0.3 nM; hD(2)K(i)=703 nM), leading to a selectivity ratio of 2343.
