Abstract
Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[bf][1,4]oxazepine), reported as a dual H-1/H-4 receptor ligand (pK(i): 8.11 (human H1R (hH(1)R)), 7.55 (human H4R (hH(4)R))), 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, ...
Abstract
Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[bf][1,4]oxazepine), reported as a dual H-1/H-4 receptor ligand (pK(i): 8.11 (human H1R (hH(1)R)), 7.55 (human H4R (hH(4)R))), 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 hH(1)R (pK(i): 6.8-8.7), but no or moderate affinity to the hH(4)R (pK(i): <= 5.3). For one oxepine derivative (1-(2-Chloro-6,11-dihydrodibenzo[b,e]oxepin-11y1)-4-methylpiperazine), the enantiomers were separated and the R-enantiomer was identified as the eutomer at the hH(1)R (pK(i): 8.83 (R), 7.63 (S)) and the guinea-pig H1R (gpH(1)R) (pK(i): 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 hH(1)R crystal structure. Moreover, docking studies of all oxepine derivatives at the hH(1)R 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 hH(1)R or hH(4)R, thus, those compounds have to be classified as dirty drugs. However, one oxazepine derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[bf]oxazepine was identified as dual hH(1)/h5-HT2A receptor ligand (pK(i): 9.23 (hH(1)R), 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 hH(1)R antagonist (pK(i): 8.44 (hH(1)R), <= 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. (C) 2016 Elsevier Ltd. All rights reserved.
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