Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists.

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Govoni M, Bakker RA, van de Wetering I, Smit MJ, Menge WM, Timmerman H, Elz S, Schunack W, Leurs R

Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists.

J Med Chem. 2003 Dec 18;46(26):5812-24.

PubMed ID

14667234 [ View in PubMed

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Abstract

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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Mepyramine	Histamine H1 receptor	IC 50 (nM)	13	N/A	N/A	Details
Tripelennamine	Histamine H1 receptor	IC 50 (nM)	40	N/A	N/A	Details