Molecular modeling studies focused on 5-HT7 versus 5-HT1A selectivity. Discovery of novel phenylpyrrole derivatives with high affinity for 5-HT7 receptors.
The present study discusses the well-known 5-HT7/5-HT1A selectivity issue through a new series of phenylpyrrole derivatives. The first hits emerged from a virtual screening performed on a chemolibrary. Further study led to an optimization of a preliminary 5-HT7 pharmacophore model. The importance of each pharmacophoric feature is confirmed, but these characteristics have to be coupled to geometric constraints in order to achieve a 5-HT7 selectivity. Indeed, 5-HT1A affinity probably arises from extended conformations, whereas a bent one appears to be best suited for 5-HT7 selectivity.
Lepailleur
Alban
A
Centre d'Etudes et de Recherche sur le Médicament de Normandie, Université de Caen, U.F.R. des Sciences Pharmaceutiques, 5 rue Vaubénard, 14032 Caen Cedex, France.
Bureau
Ronan
R
Paillet-Loilier
Magalie
M
Fabis
Frédéric
F
Saettel
Nicolas
N
Lemaître
Stéphane
S
Dauphin
François
F
Lesnard
Aurélien
A
Lancelot
Jean-Charles
JC
Rault
Sylvain
S
D019992:Databases as Topic; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry*; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D012680:Sensitivity and Specificity
C400160:3-methyl-4-phenylpyrrole; D011758:Pyrroles; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A