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 K_i 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 K_i 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 (K_i=11± nM, n=3), the α_2‐adrenoceptor (K_i=120±5 nM, n=3) and the sigma receptor (K_i=170±70 nM, n=3). Thioperamide showed relatively high affinity for the 5‐HT₃ receptor (K_i=120±30 nM, n=3) and the sigma receptor (K_i=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 α_2‐ 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 (K_i=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.