Related Experiment Videos
Unique binding pocket for KW-4679 in the histamine H1 receptor
1Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo, Sunto, Shizuoka, Japan.
European Journal of Pharmacology
|May 21, 1998
Summary
Histamine H1 receptor antagonists KW-4679 and other compounds were tested. KW-4679 shows high selectivity due to a unique binding pocket, unlike other antagonists interacting with the crucial Asp residue.
Area of Science:
- Pharmacology
- Molecular Biology
- Medicinal Chemistry
Background:
- The histamine H1 receptor possesses a conserved aspartate (Asp) residue in transmembrane helix 3 (TM3), vital for ligand binding.
- Many existing tri- and tetracyclic histamine H1 receptor antagonists lack selectivity, binding to other biogenic amine receptors.
Purpose of the Study:
- To investigate the selectivity of the novel tricyclic compound KW-4679 as a histamine H1 receptor antagonist.
- To elucidate the role of the Asp107 residue in the binding of KW-4679 and other antagonists to the histamine H1 receptor.
Main Methods:
- Radioligand binding assays using [3H]KW-4679.
- Site-directed mutagenesis to replace the Asp107 residue with alanine in the histamine H1 receptor.
- Affinity measurements for wild-type and mutant receptors with various antagonists.
Main Results:
- KW-4679 demonstrated high affinity (Kd = 2.5 nM) for wild-type human histamine H1 receptors and exhibited high selectivity.
- Mutagenesis of Asp107 significantly reduced the affinity of traditional antagonists (280-2100-fold) but only moderately affected KW-4679 (14-fold).
- This suggests that non-selective antagonists rely heavily on Asp107, while KW-4679 utilizes a distinct binding interaction.
Conclusions:
- The tested tri- and tetracyclic antagonists are not selective for the histamine H1 receptor due to their interaction with the Asp residue.
- KW-4679's high selectivity is attributed to a unique binding pocket involving Asp107 and other acceptor sites, differentiating its interaction mechanism.