Abstract
We tested several histamine H1 receptor (H1R) and antagonists for their differences in agonists binding affinities between human and guinea pig H1Rs transiently expressed in African green monkey kidney (COS-7) cells. Especially, the bivalent agonist histaprodifen-histamine dimer (HP-HA) shows a higher affinity for guinea pig than for human H1Rs. Based on the structure of HP-HA, we have further identified VUF 4669 [7-(3-(4-(hydroxydiphenylmethyl)piperidin-1-yl)propoxy)-4-oxochroman-2-carboxylic acid] as a guinea pig-preferring H1R antagonist, demonstrating that the concept of species selectivity is not limited to agonists. To delineate the molecular mechanisms behind the observed species selectivity, we have created mutant human H1Rs in which amino acids were individually replaced by their guinea pig H1R counterparts. Residue Asn84 (2.61) in transmembrane domain (TM) 2 seemed to act as a selectivity switch in the H1R. Molecular modeling and site-directed mutagenesis studies suggest that Asn84 interacts with the conserved Tyr458 (7.43) in TM7. Our data provide the first evidence that for some H1R ligands, the binding pocket is not only limited to TMs 3, 4, 5, and 6 but also comprises an additional pocket formed by TMs 2 and 7.
- Received October 29, 2004.
- Accepted December 29, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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