Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed
Authors: Leurs Rob , Tulp Martin Th.M. , Menge Wiro M.B.P. , Adolfs Martin J.P. , Zuiderveld Obbe P. , Timmerman Hendrik 
Published: July 2012

In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide.

IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)‐α‐methylhistamine‐induced inhibition of electrically‐evoked contractions of the guinea‐pig jejunum (pA2=9.12±0.06, Schild slope: 1.0±0.1, n=8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9±0.2).

In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]‐IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 ± 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1‐ and H2 receptor. Displacement of [3H]‐mepyramine and [125I]‐iodoaminopotentidine binding to respectively guinea‐pig H1‐ and human H2 receptors by IPP resulted in Ki values of 1.71±0.32 μm (n=3) and 2.28±0.81 μm (n=3). For thioperamide the affinities for the H1‐, H2‐ and H3 receptor were respectively >10 μm, >10 μm and 4.3±1.6 nM (n=7).

Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5‐hydroxytryptamine 5‐HT3 receptor (Ki=11± nM, n=3), the α2‐adrenoceptor (Ki=120±5 nM, n=3) and the sigma receptor (Ki=170±70 nM, n=3). Thioperamide showed relatively high affinity for the 5‐HT3 receptor (Ki=120±30 nM, n=3) and the sigma receptor (Ki=180±90 nM, n=3).

Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5‐HT3‐, the α2‐ and the sima receptor might interfere with [125I]‐IPP binding to rat cortex membranes. Yet, in this preparation [125I]‐IPP binding was not influenced by ondansetron, yohimbine or haloperidol.

The interaction with the 5‐HT3 receptor was not restricted to IPP or thioperamide, but was also found with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belonging to the same chemical class of IPP, also interacted with the 5‐HT3 receptor (Ki=240±40 nM). In contrast, histamine or the H3 receptor agonist, (R)‐α‐methylhistamine showed no affinity for the 5‐HT3 receptor. 7 In the guinea‐pig isolated ileum, imetit evoked concentration‐dependent contractions, resulting in a pD2 value of 4.72±0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 value of 7.1±0.1 (n=9). Similarly ondansetron antagonized the contractions evoked by the 5‐HT3 receptor agonist, 2‐methyl‐5‐HT with a pA2 value of 7.3±0.1 (n=4). IPP and thioperamide did not mimic 2‐methyl‐5‐HT but non‐competitively inhibited the 2‐methyl‐5‐HT‐induced contractions of this preparation.

In an in vivo model for 5‐HT3 activity, the Von Bezold Jarisch reflex, thioperamide showed antagonism in low dosages, which correlated well with the affinity for the 5‐HT3 receptor site. Yet, at higher dosages no further 5‐HT3 receptor antagonism was observed. For IPP no 5‐HT3 receptor activity could be observed in vivo.

In the present study we showed that many H3 receptor compounds, that are regarded as highly selective (including the prototype drug, thioperamide), also interact with the 5‐HT3 receptor, albeit at higher drug concentrations.