title: 2,4-Diaminopyrimidines as dual ligands at the histamine H1 and H4 receptor-H1/H4-receptor selectivity.
abstract: Distinct diaminopyrimidines, for example, 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine are histamine H4 receptor (H4R) antagonists and show high affinity to the H4R, but only a moderate affinity to the histamine H1 receptor (H1R). Within previous studies it was shown that an aromatic side chain with a distinct distance to the basic amine and aromatic core is necessary for affinity to the human H1R (hH1R). Thus, a rigid aminopyrimidine with a tricyclic core was used as a lead structure. There, (1) the flexible aromatic side chain was introduced, (2) the substitution pattern of the pyrimidine core was exchanged and (3) rigidity was decreased by opening the tricyclic core. Within the present study, two compounds with similar affinity in the one digit μM range to the human H1R and H4R were identified. While the affinity at the hH1R increased about 4- to 8-fold compared to the parent diaminopyrimidine, the affinity to the hH4R decreased about 5- to 8-fold. In addition to the parent diaminopyrimidine, two selected compounds were docked into the H1R and H4R and molecular dynamic studies were performed to predict the binding mode and explain the experimental results on a molecular level. The two new compounds may be good lead structures for the development of dual H1/H4 receptor ligands with affinities in the same range.
authors.affiliation: Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, D-91052 Erlangen, Germany.
authors.forename: Sebastian G
authors.initials: SG
authors.lastname: Hammer
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 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 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: Sigurd
authors.initials: S
authors.lastname: Elz
authors.affiliation: Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, D-91052 Erlangen, Germany. Electronic address: markus.heinrich@fau.de.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Heinrich
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; D002460:Cell Line; D054314:Drug Inverse Agonism; D054333:Drug Partial Agonism; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D000074040:Receptors, Histamine H4; D018411:Spodoptera
chemical_list: C418607:HRH4 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
keywords: Diaminopyrimidines; Dual H(1)R/H(4)R ligands; Histamine H(1) receptor; Histamine H(4) receptor; Molecular dynamics