This study describes the use of a naphtyl moiety as a probe to find out the steric differences in the binding sites of both alpha-1-adrenoreceptors (alpha-ARs) subtypes and 5HT1A receptor; on this ground chiral naphtyl derivatives of WB-4101 were designed, synthesized and then evaluated their binding affinities. This study brings to light the pivotal rules that probably influence the selectivity and, finally, it allows to achieve novel selective alpha-1A antagonists, that bear naphtodioxane moiety in lieu of classical benzodioxane group. The obtained results underline how the upsizing of phenoxyl substructure is negative for the affinity and/or selectivity on the alpha-1A-AR subtype, while the naphtodioxane derivatives show an affinity a bit less than WB-4101, but a selectivity profile significantly favorable. On the contrary the 1D affinity values increase as well as the upsizing of phenoxyl substructure and the 5HT1A binding values show a similar trend. A molecular modeling analysis highlights that the remarkable selectivity of naphtodioxane derivatives could be explained also on the base of its particular conformational profile, that reveals the hypothetic selective conformation for alpha-1A receptor subtype. Finally, this suggestion was verified, docking the so obtained selective conformations in the alpha-1A receptor model.
|Titolo:||The use of the naphthyl probe to scan the alpha-1A/5HT1A receptor binding sites: discovery of novel alpha-1A selective antagonists|
|Data di pubblicazione:||15-ott-2003|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Citazione:||The use of the naphthyl probe to scan the alpha-1A/5HT1A receptor binding sites: discovery of novel alpha-1A selective antagonists / C. Bolchi, R. Di Pumpo, L. Fumagalli, M. Gobbi, T. Mennini, M. Pallavicini, A. Pedretti, E. Valoti, L. Villa, G. Vistoli. ((Intervento presentato al convegno Joint Meeting on Medicinal Chemistry tenutosi a Krakow nel 2003.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|