title: Possible ligand-receptor interactions for NK1 antagonists as observed in their crystal structures.
abstract: Crystal structures of nine non-peptide tachykinin NK1 antagonists have been analysed for the intermolecular interactions of their pharmacophoric groups with neighbouring molecules in the crystals. Experimental data on interaction geometries of these antagonists with their environment can be of help in understanding the mechanism of binding to the human NK1 receptor. Several interaction geometries have been identified that are consistent with both structure-activity relationships and reported receptor interactions for the compounds analysed. In addition, an interaction site for the side-chain of Gln-165 in the human NK1 receptor that is probably involved in donating a hydrogen bond to the benzylamino nitrogen or benzylether oxygen of the quinuclidine and piperidine antagonists is explicitly postulated. Also, a superposition based on pharmacophoric elements in the crystal structure conformations of two prototypic NK1 antagonists, CP-96,345 (1) and CP-99,994 (4), suggests how both compounds might interact with the human NK1 receptor in a similar manner.
authors.affiliation: Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, The Netherlands. G.J.Boks@far.ruu.nl
authors.forename: G J
authors.initials: GJ
authors.lastname: Boks
authors.forename: J P
authors.initials: JP
authors.lastname: Tollenaere
authors.forename: J
authors.initials: J
authors.lastname: Kroon
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007546:Isoquinolines / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry*; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry*; D011812:Quinuclidines / Q000737:chemistry*; D012984:Software; D014364:Tryptophan / Q000031:analogs & derivatives*
chemical_list: D007546:Isoquinolines; D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011725:Pyridines; D011812:Quinuclidines; D014364:Tryptophan; C039109:isoquinoline