Vermeulen Erik S, Schmidt Anne W, Sprouse Jeffrey S, Wikström Håkan V, Grol Cor J
Department of Medicinal Chemistry, Center for Pharmacy, State University of Groningen, A Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
J Med Chem. 2003 Dec 4;46(25):5365-74. doi: 10.1021/jm030826m.
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.
