SYNTHESIS, X-RAY CRYSTALLOGRAPHY, AND PHARMACOKINETICS OF NOVEL AZOMETHINE PRODRUGS OF (R)-ALPHA-METHYLHISTAMINE - HIGHLY POTENT AND SELECTIVE HISTAMINE H-3 RECEPTOR AGONISTS

Since various neuroregulatory functions of the histamine H-3 receptor have been proved during the last few years, the H-3 receptor is of cur rent interest. Azomethine derivatives of the highly potent histamine H -3 receptor agonist (R)-alpha-methylhistamine (1) were prepared as lip ophilic prodrugs to improve the bioavailability of the hydrophilic dru g, particularly its entry into the brain. Additionally, azomethine der ivatization provides protection against histamine methyltransferase, t he major metabolizing enzyme in man, and thus efficiently enhances the bio availability of 1. The molecular conformations of imidazol-4-yl)- 2-propyl]-imino]phenylmethyl]phenol (9a) and -yl)-2-propyl]imino]-(4-c hlorophenyl)methyl]phenol (9p) were determined by X-ray structure anal ysis. An intramolecular hydrogen bond which is essential for the stabi lity of these azomethines was thereby confirmed. Moreover, the pharmac okinetic parameters of the prodrugs were investigated in vitro as well as in vivo. The halogenated azomethines have an effect following pero ral administration in mice, and some of them seem to be highly potent for the central nervous system (CNS) delivery of 1. At present the mos t potent prodrug of 1 is 4-yl)-2-propyl]imino](4-chlorophenyl)methyl]p henol (9q), reaching by far the highest CNS level of 1 (c(max) 71 ng/g ). Prodrugs of this type are not only valuable pharmacological tools b ut may also become Ha histaminergic drugs for therapeutic use.