Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics

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; 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.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…The number of H 3 receptor isoforms possible Vollinga et al (1994). Sharif et al (1996) Data from Harada et al (1983); Gantz et al (1991b); Leurs et al (1994aLeurs et al ( , 1995b; Sharif et al (1996) d Data from Ligneau et al, 2000;Liu et al, 2001b;Morse et al, 2001;Zhu et al, 2001;O'Reilly et al, 2002;Esbenshade et al, 2003;Thurmond et al, 2004Thurmond et al, , 2014aLim et al, 2005;Gbahou et al, 2006;Ligneau et al, 2007;Nagase et al, 2008;Zhao et al, 2008;Deml et al, 2009;Sander et al, 2009;Mowbray et al, 2011;Rossbach et al, 2011;Appl et al, 2012;Shin et al, 2012;Andaloussi et al, 2013;Savall et al, 2014 Fig. 10).…”

“…These latter compounds may allow the study of in vivo relevance of H 1 receptor constitutive antagonism, which remains to be elucidated. As with many GPCRs, the extent of H 1 receptor constitutive activity depends on the specific parameter determined Appl et al, 2012). The high Histamine Receptors constitutive activity of the H 1 receptor upon assessment of distal signaling parameters, i.e., reporter gene expression, may be explained by the fact that the concentration of effectors is limiting the cascade so that even a small number of constitutively active H 1 receptor results in a high agonist-dependent signal.…”

Naunyn-Schmiedeberg’s Archives of Pharmacology under new editorship: change and continuity

“…In fact, my most-cited publication, a review on constitutive GPCR activity (Seifert and Wenzel-Seifert 2002), has been cited 356 times so far. And several of my original publications from various areas (including papers with "negative" data) published in the journal have also been cited fairly often (see, e.g., Burde et al 1989;Seifert et al 1989;Ervens et al 1991;Appl et al 2012;Beermann et al 2012). A recently published meeting report (Heifetz et al 2015) reached more than 900 downloads within 4 months.…”

“…"Science first," academic rigor, and honesty are important characteristics of the journal. The papers by Seifert and Wenzel-Seifert (2002) and Appl et al (2012) are excellent examples for the formal flexibility of Naunyn-Schmiedeberg's Archives of Pharmacology to accommodate very complex scientific content and to present it clearly. Therefore, it is now time for me to give back to the journal the dedication that my students and I have perceived over almost three decades as authors.…”

New perspectives for a well-known biogenic amine: mast cell-derived histamine as pathophysiological agent in vincristine-induced neuropathic pain

“…It may, however, be argued that the effect of promethazine is partially due to sedative effects. Moreover, promethazine is not selective for the histamine H 1 R but also antagonizes human and guinea pig histamine H 2 receptors with a K B value in the submicromolar range (Appl et al 2012) and shows prominent anticholinergic properties. Furthermore, promethazine binds to other biogenic amine receptors, e.g., to the dopamine D 2 receptor (Seeman et al 1985) and to serotonin 5-HT 2 receptor subtypes (Fiorella et al 1995).…”