EVALUATION OF THE RECEPTOR SELECTIVITY OF THE H-3 RECEPTOR ANTAGONISTS, IODOPHENPROPIT AND THIOPERAMIDE - AN INTERACTION WITH THE 5-HT3 RECEPTOR REVEALED

1 In the present study we evaluated the receptor selectivity of the potent histamine Hg 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)-alpha-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[I-125]-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 [H-3]-mepyramine and [I-125]-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 mu M (n=3) and 2.28 +/- 0.81 mu M (n=3). For thioperamide the affinities for the H-1-, H-2 and H-3 receptor were respectively > 10 mu M, > 10 mu 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-HT3 receptor (K-i = 11 +/- 1 nM, n=3), the alpha(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). 5 Due to the low density of histamine Hg receptors in the brain, the interaction of IPP with the 5-HT3-, the alpha(2)- and the sigma receptor might interfere with [I-125]-IPP binding to rat cortex membranes. Yet, in this preparation [I-125]-IPP binding was not influenced by ondansetron, yohimbine or haloperidol. 6 The interaction with the 5-HT3 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-HT3 receptor (K-i = 240 +/- 40 nM). In contrast, histamine or the H-3 receptor agonist, (R)-alpha-methylhistamine showed no affinity for the 5-HT3 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-HT3 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-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. 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-HT3 receptor, albeit at higher drug concentrations.