Dibenzo[b,f][1,4]oxazepines and dibenzo[b,e]oxepines: Influence of the chlorine substitution pattern on the pharmacology at the HR, HR, 5-HTR and other selected GPCRs.

Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H/H receptor ligand (pK: 8.11 (human HR (hHR)), 7.55 (human HR (hHR))), 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 hHR (pK: 6.8-8.7), but no or moderate affinity to the hHR (pK:≤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 hHR (pK: 8.83 (R), 7.63 (S)) and the guinea-pig HR (gpHR) (pK: 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 hHR crystal structure. Moreover, docking studies of all oxepine derivatives at the hHR 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 hHR or hHR, 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 hH/h5-HT receptor ligand (pK: 9.23 (hHR), 8.74 (h5-HTR), ≤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 hHR antagonist (pK: 8.44 (hHR), ≤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.