The neurokinin-1 and neurokinin-2 receptor binding sites of MDL103,392 differ

• Published in: Bioorganic & medicinal chemistry 1999-12, Vol.7 (12), p.2867-2876
• Main Authors: GREENFEDER, S, CHEEWATRAKOOLPONG, B, BILLAH, M, EGAN, R. W, KEENE, E, MURGOLO, N. J, ANTHES, J. C
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites - genetics; Biological and medical sciences; COS Cells; Humans; Kinetics; Medical sciences; Models, Molecular; Mutagenesis, Site-Directed; Neurokinin-1 Receptor Antagonists; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Conformation; Pyrroles - chemistry; Pyrroles - metabolism; Pyrroles - pharmacology; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Pyrrolidines - pharmacology; Receptors, Neurokinin-1 - genetics; Receptors, Neurokinin-1 - metabolism; Receptors, Neurokinin-2 - antagonists & inhibitors; Receptors, Neurokinin-2 - genetics; Receptors, Neurokinin-2 - metabolism; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Transfection
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(99)00220-5

Several small molecule non-peptide antagonists of the NK-1 and NK-2 receptors have been developed. Mutational analysis of the receptor protein sequence has led to the conclusion that the binding site for these non-peptide antagonists lies within the bundle created by transmembrane domains IV-VII of the receptor and differs from the binding sites of peptide agonists and antagonists. The current investigation uses site-directed mutagenesis of the NK-1 and NK-2 receptors to elucidate the amino acids that are important for binding and functional activity of the first potent dual NK-1/NK-2 antagonist MDL103,392. The amino acids found to be important for MDL103,392 binding to the NK-1 receptor are Gln-165, His-197, Leu-203, Ile-204, Phe-264, His-265 and Tyr-272. The amino acids found to be important for MDL103,392 binding to the NK-2 receptor are Gln-166, His-198, Tyr-266 and Tyr-289. While residues in transmembrane (TM) domains IV and V are important in both receptors (Gln-165/166 and His-197/198), residues in TM V and VI are more important for the NK-1 receptor and residues in TM VII play a more important role in the NK-2 receptor. These data are the first report of the analysis of the binding site of a dual tachykinin receptor antagonist and indicate that a single compound (MDL103,392) binds to each receptor in a different manner despite there being a high degree of homology in the transmembrane bundles. In addition, this is the first report in which a model for the binding of a non-peptide antagonist to the NK-2 receptor is proposed.