A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha1-adrenoceptor subtypes and 5-HT1A receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolanederivative 1, previously shown to be a selective alpha1a(A)/alpha1d(D)-adrenoceptor subtype antagonist, overalpha1b(B) subtype and 5-HT1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha1/ 5-HT1A selectivity is observed, mainly due to the increase in 5-HT1A affinity. In functional experiments lactam derivatives seems to favour 5-HT1A receptor antagonism (pKb =7.20-7.80) and alpha1B-adrenoceptor antagonist selectivity (alpha1B/alpha1A and alpha1B/alpha1D of about 10-fold). Themost interesting of the various imide derivatives is compound 7t, which is a selective alpha1Dadrenoceptorantagonist (pKb = 8.1 and alpha1D/alpha1A and alpha1D/alpha1B selectivity ratios of 16 and 11respectively) whereas at 5-HT1A receptor it is a potent partial agonist (pD2 = 7.98, Emax = 60%).].Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based onmolecular docking studies was used to elucidate the atomic details of the 5HT1A /agonist and 5HT1A/antagonist interaction.

1,3-Dioxolane-Based Ligands Incorporating a Lactam or Imide moiety: Structure-Affinity/Activity Relationship at alpha1–Adrenoceptor subtypes and at 5-HT1A Receptors / Franchini, Silvia; Prandi, Adolfo; Baraldi, Anna Maria; Sorbi, Claudia; Tait, Annalisa; M., Buccioni; G., Marucci; A., Cilia; L., Pirona; P., Fossa; E., Cichero; Brasili, Livio. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 45:9(2010), pp. 3740-3751. [10.1016/j.ejmech.2010.05.023]

1,3-Dioxolane-Based Ligands Incorporating a Lactam or Imide moiety: Structure-Affinity/Activity Relationship at alpha1–Adrenoceptor subtypes and at 5-HT1A Receptors

FRANCHINI, Silvia;PRANDI, adolfo;BARALDI, Anna Maria;SORBI, Claudia;TAIT, Annalisa;BRASILI, Livio
2010

Abstract

A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha1-adrenoceptor subtypes and 5-HT1A receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolanederivative 1, previously shown to be a selective alpha1a(A)/alpha1d(D)-adrenoceptor subtype antagonist, overalpha1b(B) subtype and 5-HT1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha1/ 5-HT1A selectivity is observed, mainly due to the increase in 5-HT1A affinity. In functional experiments lactam derivatives seems to favour 5-HT1A receptor antagonism (pKb =7.20-7.80) and alpha1B-adrenoceptor antagonist selectivity (alpha1B/alpha1A and alpha1B/alpha1D of about 10-fold). Themost interesting of the various imide derivatives is compound 7t, which is a selective alpha1Dadrenoceptorantagonist (pKb = 8.1 and alpha1D/alpha1A and alpha1D/alpha1B selectivity ratios of 16 and 11respectively) whereas at 5-HT1A receptor it is a potent partial agonist (pD2 = 7.98, Emax = 60%).].Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based onmolecular docking studies was used to elucidate the atomic details of the 5HT1A /agonist and 5HT1A/antagonist interaction.
45
9
3740
3751
1,3-Dioxolane-Based Ligands Incorporating a Lactam or Imide moiety: Structure-Affinity/Activity Relationship at alpha1–Adrenoceptor subtypes and at 5-HT1A Receptors / Franchini, Silvia; Prandi, Adolfo; Baraldi, Anna Maria; Sorbi, Claudia; Tait, Annalisa; M., Buccioni; G., Marucci; A., Cilia; L., Pirona; P., Fossa; E., Cichero; Brasili, Livio. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 45:9(2010), pp. 3740-3751. [10.1016/j.ejmech.2010.05.023]
Franchini, Silvia; Prandi, Adolfo; Baraldi, Anna Maria; Sorbi, Claudia; Tait, Annalisa; M., Buccioni; G., Marucci; A., Cilia; L., Pirona; P., Fossa; E., Cichero; Brasili, Livio
File in questo prodotto:
File Dimensione Formato  
EJMedChem2010_lattami.pdf

non disponibili

Tipologia: Post-print dell'autore (bozza post referaggio)
Dimensione 746.59 kB
Formato Adobe PDF
746.59 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/641173
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 21
  • ???jsp.display-item.citation.isi??? 21
social impact