ABSTRACT
Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H1/H4 receptor ligand (pKi: 8.11 (human H1R (hH1R)), 7.55 (human H4R (hH4R))), four known and 28 new oxazepine and related oxepine derivatives were synthesised and pharmacologically characterized at histamine receptors and selected aminergic GPCRs. In contrast to the oxazepine series, within the oxepine series, the new compounds showed high affinity to the hH1R (pKi: 6.8-8.7), but no or moderate affinity to the hH4R (pKi:≤5.3). For one oxepine derivative (1-(2-Chloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine), the enantiomers were separated and the R-enantiomer was identified as the eutomer at the hH1R (pKi: 8.83 (R), 7.63 (S)) and the guinea-pig H1R (gpH1R) (pKi: 8.82 (R), 7.41 (S)). Molecular dynamic studies suggest that the tricyclic core of the compounds is bound in a similar mode into the binding pocket, as described for doxepine in the hH1R crystal structure. Moreover, docking studies of all oxepine derivatives at the hH1R indicate that the oxygen and the position of the chlorine in the tricyclic core determines, if the R- or the S-enantiomer is the eutomer. For some of the oxazepines and oxepines the affinity to other aminergic GPCRs is in the same range as to hH1R or hH4R, thus, those compounds have to be classified as dirty drugs. However, one oxazepine derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine was identified as dual hH1/h5-HT2A receptor ligand (pKi: 9.23 (hH1R), 8.74 (h5-HT2AR), ≤7 at other analysed GPCRs), whereas one oxepine derivative (1-(3,8-Dichloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine) was identified as selective hH1R antagonist (pKi: 8.44 (hH1R), ≤6.7 at other analyzed GPCRs). Thus, the pharmacological results suggest that the oxazepine/oxepine moiety and additionally the chlorine substitution pattern toggles receptor selectivity and specificity.
Subject(s)
Chlorine/chemistry , Oxazepines/pharmacology , Oxepins/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Histamine H1/metabolism , Receptors, Histamine H4/metabolism , Animals , Cells, Cultured , Guinea Pigs , Humans , Oxazepines/chemistry , Oxepins/chemistry , Protein Binding/physiology , Sf9 Cells , Structure-Activity RelationshipABSTRACT
OBJECTIVES: The purpose of this study was to compare cephalometric changes resulting from treatment with two appliances for rapid maxillary expansion: (1) a strictly tooth-borne appliance and (2) a combined tooth- and bone-borne appliance. PATIENTS AND METHODS: Pre- and posttreatment lateral cephalograms of 100 patients were analyzed by cephalometry. Of these patients, 50 were treated with strictly tooth-borne and another 50 with combined tooth- and bone-borne appliances. Mean pretreatment age was 13.04 ± 4.82 years, and mean treatment duration was 7.12 ± 2.37 months. To identify any implications for clinical therapy, additional subgroups were formed based on the pretreatment cephalometric findings for skeletal Class I (0° < ANB ≤ 4°) or Class III (ANB ≤0°). Paired t-tests were used for intragroup and analysis of variance (ANOVA) for intergroup comparisons. Results were considered statistically significant at p ≤ 0.05. RESULTS: Both appliance types resulted in significant cephalometric changes in the maxilla and mandible. Compared to the strictly tooth-borne appliances, the combined tooth- and bone-borne appliances were found to cause more pronounced advancement of the maxilla (SNA angle) notably among the Class III patients. CONCLUSIONS: Hybrid (combined tooth- and bone-borne) appliances for rapid maxillary expansion might be preferable in the treatment of skeletal Class III patients, since they possibly exert a more pronounced skeletal effect on the sagittal position of the maxilla.
