Evaluation of the receptor selectivity of the H 3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT 3 receptor revealed

1 In the present study we evaluated the receptor selectivity of the potent histamine H 3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2 IPP proved to be a potent competitive H 3 receptor antagonist as measured against (R)‐α‐methylhistamine‐induced inhibition of electrically‐evoked contractions of the guinea‐pig jejunum (pA 2 =9.12±0.06, Schild slope: 1.0±0.1, n =8). In the same assay, thioperamide was slightly less potent (pA 2 = 8.9±0.2). 3 In radioligand binding studies, IPP showed a high affinity for the H 3 receptor. Displacement of [ 125 I]‐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 H 1 ‐ and H 2 receptor. Displacement of [ 3 H]‐mepyramine and [ 125 I]‐iodoaminopotentidine binding to respectively guinea‐pig H 1 ‐ and human H 2 receptors by IPP resulted in K i values of 1.71±0.32 μ m (n=3) and 2.28±0.81 μ m ( n =3). For thioperamide the affinities for the H 1 ‐, H 2 ‐ and H 3 receptor were respectively >10 μ m , >10 μ m and 4.3±1.6 nM ( n =7). 4 Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5‐hydroxytryptamine 5‐HT 3 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‐HT 3 receptor ( K i =120±30 nM, n=3) and the sigma receptor ( K i =180±90 nM, n =3). 5 Due to the low density of histamine H 3 receptors in the brain, the interaction of IPP with the 5‐HT 3 ‐, the α 2‐ and the sima receptor might interfere with [ 125 I]‐IPP binding to rat cortex membranes. Yet, in this preparation [ 125 I]‐IPP binding was not influenced by ondansetron, yohimbine or haloperidol. 6 The interaction with the 5‐HT 3 receptor was not restricted to IPP or thioperamide, but was also found with other H 3 receptor antagonists. The potent H 3 receptor agonist imetit, a compound belonging to the same chemical class of IPP, also interacted with the 5‐HT 3 receptor ( K i =240±40 nM). In contrast, histamine or the H 3 receptor agonist, (R)‐α‐methylhistamine showed no affinity for the 5‐HT 3 receptor. 7 In the guinea‐pig isolated ileum, imetit evoked concentration‐dependent contractions, resulting in a pD 2 value of 4.72±0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA 2 value of 7.1±0.1 ( n =9). Similarly ondansetron antagonized the contractions evoked by the 5‐HT 3 receptor agonist, 2‐methyl‐5‐HT with a pA 2 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. 8 In an in vivo model for 5‐HT 3 activity, the Von Bezold Jarisch reflex, thioperamide showed antagonism in low dosages, which correlated well with the affinity for the 5‐HT 3 receptor site. Yet, at higher dosages no further 5‐HT 3 receptor antagonism was observed. For IPP no 5‐HT 3 receptor activity could be observed in vivo . 9 In the present study we showed that many H 3 receptor compounds, that are regarded as highly selective (including the prototype drug, thioperamide), also interact with the 5‐HT 3 receptor, albeit at higher drug concentrations.