title: Dibenzo[b,f][1,4]oxazepines and dibenzo[b,e]oxepines: Influence of the chlorine substitution pattern on the pharmacology at the H1R, H4R, 5-HT2AR and other selected GPCRs.
abstract: Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H1/H4receptor 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-HT2Areceptor 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.
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Naporra
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gobleder
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wittmann
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Spindler
authors.affiliation: Institute of Inorganic Chemistry, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bodensteiner
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91052 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Elz
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany. Electronic address: andrea.strasser@chemie.uni-regensburg.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002713:Chlorine / Q000737:chemistry*; D006168:Guinea Pigs; D006801:Humans; D010077:Oxazepines / Q000737:chemistry / Q000494:pharmacology*; D010082:Oxepins / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D000074040:Receptors, Histamine H4 / Q000378:metabolism*; D061987:Sf9 Cells; D013329:Structure-Activity Relationship
chemical_list: D010077:Oxazepines; D010082:Oxepins; D044402:Receptor, Serotonin, 5-HT2A; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1; D000074040:Receptors, Histamine H4; D002713:Chlorine
keywords: Dual hH(1)R/h5-HT(2A)R ligands; Dual/selective H(1)R/H(4)R ligands; Histamine H(1) receptor; Histamine H(4) receptor; Oxazepine derivatives; Oxepine derivatives