Appl, Heidrun and Holzammer, Tobias and Dove, Stefan and Haen, Ekkehard and Strasser, Andrea and Seifert, Roland (2012) Interactions of recombinant human histamine H-1, H-2, H-3, and H-4 receptors with 34 antidepressants and antipsychotics. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 385 (2). pp. 145-170. ISSN 0028-1298, 1432-1912
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Antidepressants and antipsychotics affect multiple molecular targets. Consequently, these drugs exhibit not only unique profiles of therapeutic effects but also several undesired effects. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the large family of G protein-coupled receptors and are very important drug targets. All four HxR subtypes are expressed in the CNS. Interactions of lipophilic, blood-brain barrier-penetrating drugs with H(x)Rs could contribute to therapeutic and unwanted effects. Therefore, we investigated potencies HxR as well as potencies and (inverse) agonistic efficacies of 34 antidepressants and antipsychotics at HxRs in functional assays. We expressed human H(x)Rs in Sf9 insect cells and conducted radioligand competition binding experiments and functional steady-state GTPase assays. Ligand affinities and potencies were compared with literature data and related to therapeutic reference ranges. Almost all antidepressants and antipsychotics displayed high binding affinities to H1R and behaved as antagonists. The atypical antidepressant trimipramine behaved as a high-affinity/high-potency H2R antagonist (pK(i), 7.39; pK(B), 7.36; pA(2), 7.55). Docking to an H2R model suggested a probable binding mode. The affinity of antidepressants and antipsychotics for H3R was low. The atypical antipsychotic clozapine, known to induce agranulocytosis, exhibited partial H4R agonism for which docking experiments provided a molecular basis. Clozapine also exhibited H2R antagonism. We observed dissociations between pK(i) and pK(B) values as well as between pK(i) and pIC(50) values for H(x)Rs. Antidepressants and antipsychotics interact differentially with H(x)Rs. The concept of functional selectivity (also referred to as ligand-specific receptor conformations or biased signaling) explains dissociations between pK(i) and pK(B) values as well as differences between pK(i) and pIC(50) values. The H1R antagonism of numerous antidepressants and antipsychotics is very pronounced. The H2R antagonism of trimipramine and partial H4R agonism of clozapine may be clinically relevant. We also discuss the possible role of the H2R antagonism of clozapine for neutropenia/agranulocytosis induced by this compound. Finally, we discuss the methodological, conceptual, and clinical limitations of our study.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTORS; GUINEA-PIG; CONSTITUTIVE ACTIVITY; CRYSTAL-STRUCTURE; PHARMACOLOGICAL-PROPERTIES; HEMATOLOGICAL TOXICITY; MUTATIONAL ANALYSIS; CSF CONCENTRATIONS; ANTI-DEPRESSANTS; AGONIST BINDING; Antidepressants; Antipsychotics; Trimipramine; Clozapine; Histamine receptors; Therapeutic reference range |
| Subjects: | 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 May 2020 05:28 |
| Last Modified: | 20 May 2020 05:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19298 |
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