Characterization of the 5-HT(7) receptor. Determination of the pharmacophore for 5-HT(7) receptor agonism and CoMFA-based modeling of the agonist binding site.
On the basis of a set of 20 diverse 5-HT(7) receptor agonists, the pharmacophore for 5-HT(7) receptor agonism was determined. Additionally two CoMFA models were developed, based on different alignments of the agonists. Both models show good correlations between experimental and predictive pK(i) values and show a high degree of similarity. The CoMFA fields were subsequently used to map the agonist binding site of the model of the 5-HT(7) receptor. Important roles in ligand binding are attributed to Asp162 of TM3 (interaction with a protonated nitrogen), and Thr244 of TM5 (interaction with a substituent at an aromatic moiety). Amino acid residues of the aromatic cluster of TM6 are hypothesized to play an important role in ligand binding as pi-pi stacking moieties. Agonists missing a hydrogen-bond-accepting moiety, but possessing an aromatic substituent instead, seem to bind the receptor with high affinity as well by occupying a lipophilic pocket hosted by residues of TM5 and TM6.
Vermeulen
Erik S
ES
Department of Medicinal Chemistry, Center for Pharmacy, State University of Groningen, A Deusinglaan 1, NL-9713 AV Groningen, The Netherlands. e.s.vermeulen@farm.rug.nl
Schmidt
Anne W
AW
Sprouse
Jeffrey S
JS
Wikström
Håkan V
HV
Grol
Cor J
CJ
D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011985:Receptors, Serotonin / Q000737:chemistry*; D017366:Serotonin Receptor Agonists / Q000737:chemistry*; D013764:Tetrahydronaphthalenes / Q000737:chemistry; D014363:Tryptamines / Q000737:chemistry
D008024:Ligands; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C104425:serotonin 7 receptor