Several examples support the concept that modest chemical modifications can drastically alter the biological profile of the compounds both regard to different receptor systems and inside the same system, leading to unexpected and interesting results. This consideration has prompted Boström et al. to question whether structurally similar ligands bind in a similar fashion.1 In a recent study about new 6,6-diphenyl-1,4-dioxane derivatives, we demonstrated that small modifications on the 2-phenoxyethyl moiety induced significant biological changes. In fact, the unsubstituted 1, the 2-methoxy 2, and the 2,6-dimethoxy 3 analogues proved to be endowed with high cytotossic effect, α1D-adrenergic receptor (α1D-AR) antagonist and 5-HT1A receptor full agonist activity, respectively.2 It is well known that stereochemistry can quantitatively and qualitatively influence ligand biological profile3 and that α1D- and 5-HT1A receptor interactions result highly stereospecific. Therefore, to obtain indications for identifying further structural and stereochemical requirements for selective α1D and 5-HT1A receptor recognition, we thought it of interest to prepare and test the enantiomers of 2 and 3. The enantiomers of 1 have been prepared to verify whether there is a relationship between stereochemistry and anticancer activity. 1. Boström, J.; Hogner, A.; Schmitt, S. Do structurally similar ligands bind in a similar fashion? J. Med. Chem. 2006, 49, 6716-6725. 2. Quaglia, W.; Piergentili, A.; Del Bello, F.; Farande, Y.; Giannella, M.; Pigini, M.; Rafaiani, G.; Carrieri, A.; Amantini, C.; Lucciarini, R.; Santoni, G.; Poggesi, E.; Leonardi, A. Structure-activity relationships in 1,4-benzodioxan-related compounds. 9. From 1,4-benzodioxan to 1,4-dioxane ring as a promising template of novel α1D-adrenoreceptor antagonists, 5-HT1A full agonists, and cytotoxic agents. J. Med. Chem. 2008, 51, 6359-6370. 3. Caner, H.; Groner, E.; Levy, L. Trends in the development of chiral drugs. Drug Disc. Today 2004, 9, 105-110.
Enantiomers of 6,6-diphenyl-1,4-dioxane derivatives to highlight stereochemical requirements for selective alpha1D-AR and 5- HT1A receptor recognition
DEL BELLO, FABIO;GIANNELLA, Mario;PIERGENTILI, Alessandro;PIGINI, Maria;QUAGLIA, Wilma
2009-01-01
Abstract
Several examples support the concept that modest chemical modifications can drastically alter the biological profile of the compounds both regard to different receptor systems and inside the same system, leading to unexpected and interesting results. This consideration has prompted Boström et al. to question whether structurally similar ligands bind in a similar fashion.1 In a recent study about new 6,6-diphenyl-1,4-dioxane derivatives, we demonstrated that small modifications on the 2-phenoxyethyl moiety induced significant biological changes. In fact, the unsubstituted 1, the 2-methoxy 2, and the 2,6-dimethoxy 3 analogues proved to be endowed with high cytotossic effect, α1D-adrenergic receptor (α1D-AR) antagonist and 5-HT1A receptor full agonist activity, respectively.2 It is well known that stereochemistry can quantitatively and qualitatively influence ligand biological profile3 and that α1D- and 5-HT1A receptor interactions result highly stereospecific. Therefore, to obtain indications for identifying further structural and stereochemical requirements for selective α1D and 5-HT1A receptor recognition, we thought it of interest to prepare and test the enantiomers of 2 and 3. The enantiomers of 1 have been prepared to verify whether there is a relationship between stereochemistry and anticancer activity. 1. Boström, J.; Hogner, A.; Schmitt, S. Do structurally similar ligands bind in a similar fashion? J. Med. Chem. 2006, 49, 6716-6725. 2. Quaglia, W.; Piergentili, A.; Del Bello, F.; Farande, Y.; Giannella, M.; Pigini, M.; Rafaiani, G.; Carrieri, A.; Amantini, C.; Lucciarini, R.; Santoni, G.; Poggesi, E.; Leonardi, A. Structure-activity relationships in 1,4-benzodioxan-related compounds. 9. From 1,4-benzodioxan to 1,4-dioxane ring as a promising template of novel α1D-adrenoreceptor antagonists, 5-HT1A full agonists, and cytotoxic agents. J. Med. Chem. 2008, 51, 6359-6370. 3. Caner, H.; Groner, E.; Levy, L. Trends in the development of chiral drugs. Drug Disc. Today 2004, 9, 105-110.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
