Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor

Eur J Pharmacol. 2002 Aug 9;449(3):229-37. doi: 10.1016/s0014-2999(02)02049-6.


We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • CHO Cells
  • Calcium / metabolism
  • Cloning, Molecular
  • Cricetinae
  • DNA Primers / pharmacology
  • Female
  • Histamine H1 Antagonists / metabolism
  • Histamine H1 Antagonists / pharmacology*
  • Humans
  • Kinetics
  • Loratadine / analogs & derivatives*
  • Loratadine / metabolism
  • Loratadine / pharmacology*
  • Oligonucleotides, Antisense / pharmacology
  • Pyrilamine / metabolism
  • Receptors, Histamine H1 / drug effects*
  • Receptors, Histamine H1 / metabolism


  • DNA Primers
  • Histamine H1 Antagonists
  • Oligonucleotides, Antisense
  • Receptors, Histamine H1
  • Loratadine
  • desloratadine
  • Pyrilamine
  • Calcium