4 Displacement studies with histamine showed that a limited fraction (32 ± 6%) of the binding sites showed a high affinity for histamine (2 ± 1.2 gM); the shallow displacement curves were reflected by a Hill-coefficient significantly different from unity (nH = 0.58 ± 0.09). The addition of 100 ILM Gpp(NH)p resulted in a steepening of the displacement curve (nH = 0.79 ± 0.02) and a loss of high affinity sites for histamine. 5 Displacement studies with other agonists indicated that the recently developed specific H2 agonists, amthamine and amselamine, showed an approximately 4-5 fold higher affinity for the human H2 receptor than histamine. 6 Stimulation of CHOhumH2 cells with histamine resulted in a rapid rise of the intracellular cyclic AMP levels. After 10 min an approximately 10 fold increase in cyclic AMP could be measured. The EC50 value for this response was 7 ± 1 nM for histamine. This response was effectively blocked by tiotidine and cimetidine, resulting in Ki values of 8 ± 1 nM and 0.56 ± 0.24 LM respectively.
1 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. 2 IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-amethylhistamine-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). histamine or the H3 receptor agonist, (R)-a-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. 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 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.
In the present study we searched for neutral antagonists for the human histamine H(1)-receptor (H(1)R) by screening newly synthesized ligands that are structurally related to H(1)R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-kappaB driven reporter-gene assay that allows for the detection of both agonistic and inverse agonistic responses. Starting from the endogenous agonist for the H(1)R, histamine, we synthesized and tested various analogues and ultimately identified several compounds with partial inverse agonistic properties and two neutral H(1)-receptor antagonists, namely 2-[2-(4,4-diphenylbutyl)-1H-imidazol-4-yl]ethylamine (histabudifen, 18d) (pK(i) = 5.8, alpha = 0.02) and 2-[2-(5,5-diphenylpentyl)-1H-imidazol-4-yl]ethylamine (histapendifen, 18e) (pK(i) = 5.9, alpha = -0.09).
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