title: Novel potent 5-HT(3) receptor ligands based on the pyrrolidone structure. Effects of the quaternization of the basic nitrogen on the interaction with 5-HT(3) receptor.
abstract: The results of a comprehensive structure-affinity relationship study on the effect of the quaternization (i.e., N-methylation) of structurally different ligands in the classes of tropane and quinuclidine derivatives are described. This study shows that the effects of the quaternization of the basic nitrogen of these 5-HT(3) receptor ligands appear to be strictly structure-dependent suggesting that different binding modes are operative at 5-HT(3) receptor binding site. The different effect of the quaternization of the basic nitrogen of structurally different ligands were rationalized in terms of the interaction with the receptor by means of the combined use of experimental techniques (X-ray diffraction and NMR studies) and computational simulation studies.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Gallelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Braile
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Menziani
authors.forename: Pier G
authors.initials: PG
authors.lastname: De Benedetti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Donati
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D018360:Crystallography, X-Ray; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds; D011812:Quinuclidines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000737:chemistry*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D008024:Ligands; D011760:Pyrrolidinones; D000644:Quaternary Ammonium Compounds; D011812:Quinuclidines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D014326:Tropanes