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.
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.
Cappelli
Andrea
A
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
Gallelli
Andrea
A
Braile
Carlo
C
Anzini
Maurizio
M
Vomero
Salvatore
S
Mennuni
Laura
L
Makovec
Francesco
F
Menziani
M Cristina
MC
De Benedetti
Pier G
PG
Donati
Alessandro
A
Giorgi
Gianluca
G
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
D008024:Ligands; D011760:Pyrrolidinones; D000644:Quaternary Ammonium Compounds; D011812:Quinuclidines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D014326:Tropanes