PMID- 15626750
OWN - NLM
STAT- MEDLINE
DCOM- 20050420
LR  - 20131121
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 67
IP  - 4
DP  - 2005 Apr
TI  - Pharmacological differences between human and guinea pig histamine H1 receptors: 
      Asn84 (2.61) as key residue within an additional binding pocket in the H1 
      receptor.
PG  - 1045-52
AB  - We tested several histamine H(1) receptor (H(1)R) and antagonists for their 
      differences in agonists binding affinities between human and guinea pig H(1)Rs 
      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 H(1)Rs. 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 H(1)R 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 
      H(1)Rs in which amino acids were individually replaced by their guinea pig H(1)R 
      counterparts. Residue Asn(84) (2.61) in transmembrane domain (TM) 2 seemed to act 
      as a selectivity switch in the H(1)R. Molecular modeling and site-directed 
      mutagenesis studies suggest that Asn(84) interacts with the conserved Tyr(458) 
      (7.43) in TM7. Our data provide the first evidence that for some H(1)R 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.
FAU - Bruysters, Martijn
AU  - Bruysters M
AD  - Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Department of 
      Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV 
      Amsterdam, The Netherlands.
FAU - Jongejan, Aldo
AU  - Jongejan A
FAU - Gillard, Michel
AU  - Gillard M
FAU - van de Manakker, Frank
AU  - van de Manakker F
FAU - Bakker, Remko A
AU  - Bakker RA
FAU - Chatelain, Pierre
AU  - Chatelain P
FAU - Leurs, Rob
AU  - Leurs R
LA  - eng
PT  - Journal Article
DEP - 20041230
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Histamine Agonists)
RN  - 0 (Histamine H1 Antagonists)
RN  - 0 (Receptors, Histamine H1)
RN  - HPE317O9TL (Pyrilamine)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Guinea Pigs
MH  - Histamine Agonists/*metabolism
MH  - Histamine H1 Antagonists/*metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Mutagenesis, Site-Directed
MH  - Pyrilamine/metabolism
MH  - Receptors, Histamine H1/chemistry/*metabolism
MH  - Species Specificity
MH  - Structure-Activity Relationship
EDAT- 2005/01/01 09:00
MHDA- 2005/04/21 09:00
CRDT- 2005/01/01 09:00
PHST- 2005/01/01 09:00 [pubmed]
PHST- 2005/04/21 09:00 [medline]
PHST- 2005/01/01 09:00 [entrez]
AID - mol.104.008847 [pii]
AID - 10.1124/mol.104.008847 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2005 Apr;67(4):1045-52. doi: 10.1124/mol.104.008847. Epub 2004 Dec 
      30.