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 a1-adrenoceptor subtypes and 5-HT1A receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective a1a(A)/a1d(D)-adrenoceptor subtype antagonist, over a1b(B) subtype and 5-HT1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of a1/5-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 ¼ 7.20e7.80) and a1B-adrenoceptor antagonist selectivity (a1B/a1A and a1B/a1D of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective a1D-adrenoceptor antagonist (pKb ¼ 8.1 and a1D/a1A and a1D/a1B selectivity ratios of 16 and 11 respectively) whereas at 5-HT1A receptor it is a potent partial agonist (pD2 ¼ 7.98, Emax ¼ 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular 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 alpha(1)-adrenoceptor subtypes and at 5-HT(1A) receptors.

FOSSA, PAOLA;CICHERO, ELENA;
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 a1-adrenoceptor subtypes and 5-HT1A receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective a1a(A)/a1d(D)-adrenoceptor subtype antagonist, over a1b(B) subtype and 5-HT1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of a1/5-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 ¼ 7.20e7.80) and a1B-adrenoceptor antagonist selectivity (a1B/a1A and a1B/a1D of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective a1D-adrenoceptor antagonist (pKb ¼ 8.1 and a1D/a1A and a1D/a1B selectivity ratios of 16 and 11 respectively) whereas at 5-HT1A receptor it is a potent partial agonist (pD2 ¼ 7.98, Emax ¼ 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT1A/agonist and 5HT1A/antagonist interaction.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/294503
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