Molecular modeling study of 4-phenylpiperazine and 4-phenyl-1,2,3,6-tetrahydropyridine derivatives: a new step towards the design of high-affinity 5-HT1A ligands.
The main feature of many drugs having a 5-HT(1A) affinity is the presence of an arylpiperazine moiety. Indeed, the protonated nitrogen and the aromatic ring of the arylpiperazine compounds are considered crucial for the interaction with the receptor. However, the replacement of the piperazine moiety by a 1,2,3,6-tetrahydropyridine ring in 4-arylpiperazine-ethyl carboxamide derivatives was recently shown to be highly favourable for 5-HT(1A) affinity. In order to better understand the favourable effect of this chemical modification, we performed a conformational analysis of these compounds mainly based on the position of the phenyl ring relative to the piperazine and tetrahydropyridine moiety. In the piperazine compounds, the phenyl ring preferentially adopts a perpendicular orientation, whereas an almost planar orientation seems to be the most favourable conformation for the tetrahydropyridine compounds. Therefore, this conformational difference appears as a key for a better interaction with the receptor binding site. This result will serve for the designing high-affinity 5-HT(1A) ligands.
Dilly
Sébastien
S
Laboratory of Medicinal Chemistry, Drug Research Center, University of Liège, Avenue de l'Hôpital, 1 B36, B-4000 Liège 1, Belgium.
Graulich
Amaury
A
Liégeois
Jean-François
JF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism*
C472242:DR-4004; D007211:Indoles; D008024:Ligands; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine