Giovannella Strappaghetti

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.

α1-Adrenoceptor antagonists. 5. Pyridazinone-arylpiperazines. Probing the influence on affinity and selectivity of both ortho-Alkoxy groups at the arylpiperazine moiety and cyclic substituents at the pyridazinone nucleus

Our previous work on pyridazinone-arylpiperazine derivatives suggested some structural features that a compound should have to show high affinity and good selectivity for alpha(1) adrenoceptors (AR) with respect to alpha(2)-AR. Accordingly, two classes of new alkoxyphenylpiperazinylheptylpyridazinones were designed and synthesized to evaluate the effect of the alkoxy substituent on affinity and selectivity. As expected, affinity increased with larger alkoxy groups. Affinity values are all comparable with that of the reference compound (prazosin), with the exception of compound 1c found 4.5-fold more active than prazosin.

α1-Adrenoceptor antagonists. Rational design, synthesis and biological evaluation of new trazodone-like compounds

A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.

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.

New pyridazinones: synthesis and correlation between structure and α-blocking activity

Abstract The synthesis of a series of 5-(4-piperazinyl)-3(2 H )-pyridazinone has been reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferens.

Synthesis and pharmacological activity of some new pyridazinones

Abstract The synthesis of a series of piperazinyl-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferens. For compounds 7, 17 and 18, the hypotensive activity was also evaluated.

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.

“Novel and Highly Selective Postsynaptic α-Adrenoreceptor Antagonists: Synthesis and Structure-Activity Relationships of Alkane-Bridged [4-(phenoxyethyl)-1-piperazinyl]-3 (2H)-pyridazinones”.

Summary The synthesis of selected 4-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones and alkane-bridged dimers of 4-, 5- and 6-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferons.

New pyridazinone derivatives as inhibitors of platelet aggregation

Summary The synthesis and evaluation of the biological activity of a series of 3(2 H )-pyridazinone derivatives is reported. We assessed the in vitro activity of these compounds on aggregation and production of thromboxane A 2 and prostaglandin E 2 of human platelets. In compounds 11 and 14 the 3-phenylpropyl group is N -linked to the 2 position of the pyridazinone ring of 6-(1 H -imidazolel-yl)-3(2 H )-pyndazinone 3 or 6-[4-(1 H -imidazole-1-yl)-phenyl]-3(2 H )-pyridazinone 4 , respectively. These compounds inhibited platelet aggregation induced by arachidonic acid, ADP and collagen, and simultaneously suppressed the synthesis of TxA 2 and increased the production of PGE 2 . These results characterize compounds 11 and 14 as thromboxane synthase inhibitors. However, the inhibition of platelet aggregation induced by U46619 and of the first wave of ADP-induced aggregation, which is not normally observed with thromboxane synthase inhibitors, suggests additional mechanisms of action for our compounds. On the basis of structural similarities with compounds described previously, these are possibly related to a phosphodiesterase inhibitory activity.

Synthesis and biological affinity of new imidazo- and indol-arylpiperazine derivatives: Further validation of a pharmacophore model for α1-adrenoceptor antagonists

In the continuing search for selective alpha(1)-adrenoceptor (AR) antagonists, new alkoxyarylpiperazinylalkylpyridazinone derivatives were designed and synthesized. The new compounds were tested for their affinity toward alpha(1)-AR, alpha(2)-AR and 5-HT(1A) receptors. The ability of these compounds to inhibit the serotonin transporters (SERT) was also determined. The pharmacological data confirm that increasing the size of the ortho alkoxy substituent on the phenyl ring of the arylpiperazine moiety afforded compounds with enhanced affinity toward the alpha(1)-AR. The isopropoxy group, the largest group evaluated, led the best alpha(1)-AR affinity profile. In contrast, the compounds which have an amide group within of the o-alkoxy-phenylpiperazine fragment showed low affinity toward the receptors studied. Similar results were obtained when the amide group was present in the linker of the junction between the two major constituents of the molecule.