Abstract
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; 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 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.
Abbreviations
- pEC50 :
-
Negative decadic logarithm of the agonist concentration which induces 50% of the maximum stimulation
- pIC50 :
-
Negative decadic logarithm of inverse agonist concentration which induces 50% of the maximum inhibition
- E max :
-
Maximum response relative to histamine (1.00)
- DMSO:
-
Dimethyl sulfoxide
- GPCR:
-
G protein-coupled receptor
- h:
-
Human
- gpH2R-GsαS :
-
Fusion protein of the guinea pig histamine H2R and the short splice variant of Gsα
- hβ2AR:
-
Human β2 adrenoceptor
- H1R:
-
Histamine H1 receptor
- H2R:
-
Histamine H2 receptor
- hH2R-GsαS :
-
Fusion protein of the human histamine H2R and the short splice variant of Gsα
- hH3R:
-
Human histamine H3 receptor
- hH4R:
-
Human histamine H4 receptor
- H x R:
-
Non-specified histamine receptor subtype
- TM:
-
Transmembrane domain
- pK B :
-
Negative decadic logarithm of the inhibition constant of an antagonist/inverse agonist calculated from functional assays (steady-state GTPase assays in our case)
- K D :
-
Equilibrium dissociation constant calculated from radioligand saturation binding assays
- pK D :
-
Negative decadic logarithm of the equilibrium dissociation constant calculated from radioligand saturation binding assays
- pK i :
-
Negative decadic logarithm of the inhibition constant calculated from radioligand competition binding assays
- pA 2 :
-
negative decadic logarithm of the concentration of antagonist that causes a concentration ratio of agonist of r = 2 in a functional assay (steady-state GTPase in our case)
- TCA:
-
Tricyclic antidepressant
- RGS protein:
-
Regulator of G protein signaling protein
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Acknowledgments
We thank G. Wilberg for her competent help with the cell culture. This project was supported by Deutsche Forschungsgemeinschaft Graduate Training Program 760 (R.S.), Deutsche Forschungsgemeinschaft research grant STR 1125/1-1 (A.S.), and the European Union COST program BM0806 (A.S. and R.S.). We also appreciate the most valuable critique and suggestions of the reviewers.
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Appl, H., Holzammer, T., Dove, S. et al. Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics. Naunyn-Schmiedeberg's Arch Pharmacol 385, 145–170 (2012). https://doi.org/10.1007/s00210-011-0704-0
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DOI: https://doi.org/10.1007/s00210-011-0704-0