Roberta Barbaro

Synthesis and biological activity of new 1,4-benzodioxan-arylpiperazine derivatives. Further validation of a pharmacophore model for α1-Adrenoceptor antagonists

A series of WB4101 (1)-related benzodioxanes (2-17) have been synthesized by replacing the phenoxyethyl moiety of 1 with a N-alkyl piperazine bearing a cyclic substituent (a substituted or unsubstituted phenyl group, a pyridine or pyridazinone ring, a furoyl moiety) at the second nitrogen atom. The binding profile of these compounds has been assessed by radioligand receptor binding assay at alpha(1)- and alpha(2)-adrenoceptors, in comparison to prazosin and rauwolscine, respectively. Moreover, structure-activity relationships have been derived for compounds 2-17 based on their fitting to a pharmacophore model for alpha(1)-adrenoceptor antagonists recently proposed by our research group. In a parallel way, the same compounds have been used to further test the predictive power and statistical significance of the model itself. The accuracy of the results obtained also in this case revealed the robustness of the calculated pharmacophore model and led to the identification of the molecular structural moieties which are thought to contribute to the biological activity.

Adenosine receptors : Synthesis, structure-activity relationships and biological activity of new 6-amino purine derivatives

Abstract The synthesis and evaluation of the biological activity of a series of pyridazin-3(2H)-one derivatives is reported. The compounds were tested in radioligand binding assays for affinity at A, and A 2A adenosine receptors in bovine brain cortical membranes, and bovine brain striatal membranes, respectively. None of the compounds shows any affinity towards A 2A receptor, while compounds in which the 6-chloro-pyridazin-3(2H)-one or 6-phenyl-pyridazin-3(2H)-one group is linked through a chain of two carbon atoms in the 6 position of the adenosine, show a good affinity towards A 1 adenosine receptor, particularly compound 8 in which a phenyl-pyridazinone group is present shows highest affinity with K i values 6.6 nM.

Structure–activity relationships in a series of 8-substituted xanthines as A1-adenosine receptor antagonists

A series of 8-substituted xanthines were synthesized and their affinity in vitro towards A1, A2A-adenosine receptors was evaluated by radioligand receptor binding assays. All compounds showed a greater affinity and selectivity towards the A1-adenosine receptor than theophylline. The compounds in which the n-proyl group is in 1-position of the xanthine nucleus and the pyridazinone system in 8-position is linked through a chain of two or four carbon atoms, showed the highest affinity and selectivity.

Comparative molecular field analysis of some pyridazinone-containing α1-Antagonists

Diverse series of piperazines linked at N1 to 4, 5, or 6 positions of 3-(2H)-pyridazinone ring and at N4, by a suitable alkyl spacer, to some classical alpha1-adrenoceptor pharmacophore moieties, were tested in vitro for their alpha1-adrenoceptor antagonist activity. The modeling of their biological activity (pKb) by comparative molecular field analysis led to the development of a statistically significant partial least squares (PLS) model able to detect at 3-D level the main physicochemical interactions responsible for alpha1-adrenoceptor antagonist activity.

Synthesis of new pyridazinone derivatives and their affinity towards α1–α2-adrenoceptors

Abstract A series of 3(2H)-pyridazinone derivatives was evaluated for their affinity in vitro towards α1–α2-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the α1-adrenoceptor (with Ki values in the subnanomolar range), and a gradual increase in affinity was observed by increasing the polymethylene chain length of this series up to a maximum of six and seven carbon atoms, when the fragment 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl is linked in 5 position of the 3(2H)-pyridazinone ring, while a slight decrease was found for the higher homologues. Increasing the chain length when the 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl group is linked in 6 position of the 3(2H)-pyridazinone ring, had a different effect: there is the highest affinity when the polymethylene chain is of four carbon atoms. The alkylic chain, a spacer between the two major constituents of the molecule, can influence the affinity and the selectivity.

New 3(2H)-pyridazinone derivatives: synthesis and affinity towards α1AR subtypes and 5HT1A receptors

Summary The synthesis and the evaluation of the radioreceptor binding affinity of a series of 3(2 H )-pyridazinone derivatives is reported. Their affinity towards the α 1 receptor, three α 1 -AR subtype (α 1a /α 1b /α 1d ) receptors and the 5HT 1A receptor has been determined. The results of the affinity on α 1 -AR subtypes and the 5HT 1A /α 1 selectivity are discussed.

Synthesis and α1-antagonist activity of derivatives of 4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone

Abstract The synthesis and evaluation of the biological activity of new 4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone derivatives are reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoceptors of isolated rat vas deferens.

Photochemical Cleavage of Supercoiled DNA by N-Acyloxypyridine-2-thione Acridinyl Derivatives

New acyl thiohydroxamates bearing an acridine moiety able to intercalate DNA double strand exhibit the capacity to cleave supercoiled DNA to linear DNA. EPR spin-trapping analysis has been employed to detect the formation of the carbon-centered radicals.