| Abstract
| - The synthesis and biological evaluation of a series of new derivatives of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), are reported. Chemical andpharmacological studies on compounds 6 have been pursued with the aim of expanding theSAR data and validating the previously proposed model of interaction of this class of compoundswith the κ-opioid receptor. The synthesis of the previously described compounds 6 has beenreinvestigated in order to obtain a more direct synthetic procedure. To study the relationshipbetween the stereochemistry and the receptor binding affinity, compounds 6e and 6k wereselected on the basis of their evident structural resemblance to tifluadom. Since a differentspecificity of action could be expected for the enantiomers of 6e and 6k, owing to the resultsshown by (S)- and (R)-tifluadom, their racemic mixtures have been resolved by means of liquidchromatography with chiral stationary phases (CSP), and the absolute configuration of theenantiomers has been studied by circular dichroism (CD) and 1H NMR techniques. Moreover,some new 2-[(acylamino)ethyl]-1,4-benzodiazepine derivatives, 6a−d,f,g,j, have been synthesized, while the whole series (6a−o) has been tested for its potential affinity toward humancloned κ-opioid receptor. The most impressive result obtained from the binding studies lies inthe fact that this series of 2-[2-(acylamino)ethyl]-1,4-benzodiazepine derivatives binds thehuman cloned κ-opioid receptor subtype very tightly. Indeed, almost all the ligands withinthis class show subnanomolar Ki values, and the least potent compound 6o shows, in any case,an affinity in the nanomolar range. A comparison of the affinities obtained in human clonedκ-receptor with the correspondent one obtained in native guinea pig κ-receptor suggests thatthe human cloned κ-receptor is less effective in discriminating the substitution pattern thanthe native guinea pig κ-receptor. Furthermore, the results obtained are discussed with respectto the interaction with the homology model of the human κ-opioid receptor, built on the recentlysolved crystal structure of rhodopsin. Finally, the potential antinociceptive and antiamnesicproperties of compounds 6e and 6i have been investigated by means of the hot-plate and passiveavoidance test in mice, respectively.
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