Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics.

Appl, Heidrun, Holzammer, Tobias, Dove, Stefan, Haen, Ekkehard, Strasser, Andrea und Seifert, Roland (2012) Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics. Naunyn-Schmiedeberg's archives of pharmacology 385 (2), S. 145-170.

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Zusammenfassung

Zusammenfassung

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 H(x)R 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 H(x)R 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; pA₂, 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 pIC₅₀ 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 pIC₅₀ 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.

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Dokumentenart:

Artikel

Datum:

2012

Institutionen:

Medizin > Lehrstuhl für Psychiatrie und Psychotherapie
Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmazeutische / Medizinische Chemie II (Prof. Buschauer)

Projekte:

GRK 760, Graduiertenkolleg Medizinische Chemie

Identifikationsnummer:

Wert	Typ
22033803	PubMed-ID
10.1007/s00210-011-0704-0	DOI

Klassifikation:

Notation	Art
Antidepressive Agents/metabolism	MESH
Antipsychotic Agents/metabolism	MESH
Binding, Competitive	MESH
Histamine Agonists/metabolism	MESH
Histamine Antagonists/metabolism	MESH
Humans	MESH
Models, Molecular	MESH
Protein Binding	MESH
Radioligand Assay	MESH
Receptors, Histamine/metabolism	MESH
Recombinant Proteins/metabolism	MESH

Dewey-Dezimal-Klassifikation:

500 Naturwissenschaften und Mathematik > 540 Chemie
600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin
600 Technik, Medizin, angewandte Wissenschaften > 615 Pharmazie

Status:

Veröffentlicht

Begutachtet:

Ja, diese Version wurde begutachtet

An der Universität Regensburg entstanden:

Eingebracht am:

15 Nov 2012 09:29

Zuletzt geändert:

15 Nov 2012 14:44

Dokumenten-ID:

26718

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