Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345.

Abstract

Substance P is a peptide neurotransmitter that binds to the neurokinin-1 receptor and is involved in pain transmission and neurogenic inflammation. Recently, a non-peptide substance P antagonist (CP 96345) has been shown to be effective in animal models of pain and inflammation. An understanding of the molecular interactions responsible for ligand binding will be critical for the development of more specific and selective antagonists for the neurokinin-1 receptor and for the discovery of new antagonists for related G-protein-coupled receptors. Here we report that histidine at position 197 in the fifth transmembrane helix of the human neurokinin-1 receptor binds specifically to CP 96345 but not to peptide agonists. Substitution of His 197 by different amino acids and analysis of structural analogues of antagonists suggest that His 197 is involved in an amino-aromatic interaction with the benzhydryl moiety of CP 96345.

• Authors: T M Fong, M A Cascieri, H Yu, A Bansal, C Swain, C D Strader
• Journal: Nature (Nature) Vol. 362 Issue 6418 Pg. 350-3 (Mar 25 1993) ISSN: 0028-0836 [Print] England
• PMID: 8384323 (Publication Type: Journal Article)

Chemical References

• Biphenyl Compounds
• Hypnotics and Sedatives
• Receptors, Neurokinin-2
• Receptors, Neurotransmitter
• Histidine
• Neurokinin A
• CP 96345

Topics

• Amino Acid Sequence
• Biphenyl Compounds (chemistry)
• Histidine
• Humans
• Hypnotics and Sedatives (chemistry)
• Molecular Sequence Data
• Neurokinin A (chemistry)
• Point Mutation
• Receptors, Neurokinin-2
• Receptors, Neurotransmitter (chemistry)