Molecular determinants of peptide and nonpeptide NK-2 receptor antagonists binding sites of the human tachykinin NK-2 receptor by site-directed mutagenesis.
A series of 14 mutants on nine selected residues of the human tachykinin NK(2) receptor was produced and stably transfected into CHO cells to investigate the binding of the peptide MEN 11420 and the nonpeptide SR 48968 antagonists. The main interactions found for MEN 11420 were with Thr171, Tyr206, Tyr266 and Phe270. In the case of SR 48968 crucial residues were Tyr266 and Tyr289. While some overlapping of the binding sites exists, the binding modes suggested by this study appear not to allow structural correlation, and therefore general SAR, between these two antagonists.
Giolitti
A
A
Department of Drug Design, Menarini Ricerche, Via Sette Santi 3, Firenze, Italy. agiolitti@menarini-ricerche.it
Cucchi
P
P
Renzetti
A R
AR
Rotondaro
L
L
Zappitelli
S
S
Maggi
C A
CA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D015288:Neurokinin A / Q000378:metabolism; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D017354:Point Mutation; D011485:Protein Binding; D011869:Radioligand Assay; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
D001549:Benzamides; C107754:MEN 11420; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C073839:SR 48968; D015288:Neurokinin A