Constitutive activity of the histamine H(1) receptor reveals inverse agonism of histamine H(1) receptor antagonists.
Transient expression of the wild-type human histamine H(1) receptor in SV40-immortalised African green monkey kidney cells resulted in an agonist-independent elevation of the basal levels of the second messenger inositoltrisphospate. Several histamine H(1) receptor antagonists, including the therapeutically used anti-allergics cetirizine, loratadine and epinastine reduced this constitutive histamine H(1) receptor activity. Inverse agonism, i.e., stabilisation of an inactive conformation of the human histamine H(1) receptor, may therefore be a key component of the anti-allergic mechanism of action of clinically used antihistamines.
Bakker
R A
RA
Department of Pharmacochemistry, Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, Netherlands.
Wieland
K
K
Timmerman
H
H
Leurs
R
R
D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002461:Cell Line, Transformed; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000378:metabolism / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008762:Methylhistidines / Q000494:pharmacology; D011738:Pyrilamine / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D007295:Inositol Phosphates; D008762:Methylhistidines; D011969:Receptors, Histamine H1; D011993:Recombinant Fusion Proteins; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D011738:Pyrilamine