Phe369(7.38) at human 5-HT(7) receptors confers interspecies selectivity to antagonists and partial agonists.

British Journal of Pharmacology
Thibault VarinJordi Rodrigo

Abstract

Human and rat 5-HT(7) receptors were studied with a particular emphasis on the molecular interactions involved in ligand binding, searching for an explanation to the interspecies selectivity observed for a set of compounds. We performed affinity studies, molecular modelling and site-directed mutagenesis, with special focus on residue Phe(7.38) of the human 5-HT(7) receptor [Cys(7.38) in rat]. Competition binding studies were performed for seven 5-HT(7) receptor ligands at three different 5-HT(7) receptors. The functional behaviour was evaluated by measuring 5-carboxytryptamine-stimulated cAMP production. Computational simulations were carried out to explore the structural bases in ligand binding observed for these compounds. Competition experiments showed a remarkable selectivity for the human receptor when compared with the rat receptor. These results indicate that mutating Cys to Phe at position 7.38 profoundly affects the binding affinities at the 5-HT(7) receptor. Computational simulations provide a structural interpretation for this key finding. Pharmacological characterization of compounds mr25020, mr25040 and mr25053 revealed a competitive antagonistic behaviour. Compounds mr22423, mr22433, mr23284 and mr25052 behaved as...Continue Reading

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Citations

Apr 26, 2014·European Journal of Medicinal Chemistry·Gilberto SpadoniPatrizia Minetti
Feb 4, 2014·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Daniel SzulczykMarta Struga
Jan 30, 2013·Biochemical Society Transactions·Hugo Gutiérrez-de-TeránDavid Rodríguez
Sep 17, 2013·ChemMedChem·Jeeyeon KimHyunah Choo
Oct 4, 2019·European Journal of Medicinal Chemistry·Sangeetha-Laura ThirumaranChristophe Rochais

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