Synthesis and biological affinity of new imidazo- and indol-arylpiperazine derivatives: further validation of a pharmacophore model for alpha(1)-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.

A genetic-function-approximation-based QSAR model for the affinity of arylpiperazines toward alpha1 adrenoceptors.

The genetic function approximation (GFA) algorithm has been used to derive a three-term QSAR equation able to correlate the structural properties of arylpiperazine derivatives with their affinity toward the alpha1 adrenoceptor (alpha1-AR). The number of rotatable bonds, the hydrogen-bond properties, and a variable belonging to a topological family of descriptors (chi) showed significant roles in the binding process toward alpha1-AR. The new model was also compared to a previous pharmacophore for alpha1-AR antagonists and a QSAR model for alpha2-AR antagonists with the aim of finding common or different key determinants influencing both affinity and selectivity toward alpha1- and alpha2-AR.

New 4-(4-methyl-phenyl)phthalazin-1(2H)-one derivatives and their effects on alpha1-receptors.

Continuing our research aimed at obtaining new compounds with high affinity and selectivity toward alpha(1)-AR, a new series of arylpiperazine derivatives was designed, synthesized, and biologically tested. The new compounds 1-17 are characterized by a phenylphthalazin-1(2H)-one fragment connected through an alkyl chain to an arylpiperazine residue. The pharmacological profile of these compounds was evaluated for their affinity and selectivity toward alpha(1)-AR, alpha(2)-AR and toward 5HT(1A) serotoninergic receptor. A discussion on the structure-activity relationship (SAR) of these compounds is also reported.

Synthesis of new piperazine-pyridazinone derivatives and their binding affinity toward alpha1-, alpha2-adrenergic and 5-HT1A serotoninergic receptors.

We report the design and synthesis of a new class of piperazine-pyridazinone analogues. The arylpiperazine moiety, the length of the spacer, and the terminal molecular fragment were varied to evaluate their influence in determining the affinity of the new compounds toward the alpha1-adrenergic receptor (alpha1-AR), alpha2-adrenergic receptor (alpha2-AR), and the 5-HT1A serotoninergic receptor (5-HT1AR). Biological data showed that most of the compounds have an alpha1-AR affinity in the nanomolar or subnanomolar range, while affinity toward the other two receptors was lower in most cases. However, several of the tested compounds also showed very good (in the nanomolar range) or moderate affinity toward the 5-HT1AR subtype.

Design, synthesis, and alpha(1)-adrenoceptor binding properties of new arylpiperazine derivatives bearing a flavone nucleus as the terminal heterocyclic molecular portion.

Following our research project aimed at obtaining new compounds with high affinity and selectivity toward alpha(1)-adrenoceptors (AR), a new class of piperazine derivatives was designed, synthesized and biologically tested. The new compounds 1-13 are characterized by a flavone system linked, through an ethoxy or propoxy spacer, to a phenyl- or pyridazinone-piperazine moiety. Biological data showed an interesting profile for the phenylpiperazine subclass found to have a nanomolar affinity toward alpha(1)-AR, and less pronounced affinity for alpha(2)-AR and the 5-HT(1A) serotoninergic receptor. A discussion on the structure-activity relationship (SAR) of such compounds is also reported, on the basis of the flavone substitution pattern, length and functionalization of the spacer, and disruption of the phenylpiperazine system.

Alpha1-adrenoceptor antagonists. 6. Structural optimization of pyridazinone-arylpiperazines. Study of the influence on affinity and selectivity of cyclic substituents at the pyridazinone ring and alkoxy groups at the arylpiperazine moiety.

In continuing our search for selective alpha(1)-adrenoceptor (AR) antagonists, we have synthesized new alkoxyarylpiperazinylalkylpyridazinone derivatives. The new compounds were tested for their affinity toward alpha(1)- and alpha(2)-AR and toward the 5-HT(1A) receptor. alpha(1)-AR affinity data are in the subnanomolar range, with 3 showing an affinity of 0.052 nM, about 5-fold higher than prazosin. None of the studied compounds was found to be alpha(1)/alpha(2) selective, but 8 showed an interesting 5-HT(1A)/alpha(1) affinity ratio of 119.

alpha1-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.

Alpha(1)-adrenoceptor antagonists. 4. Pharmacophore-based design, synthesis, and biological evaluation of new imidazo-, benzimidazo-, and indoloarylpiperazine derivatives.

As a part of a program aimed at discovering compounds endowed with alpha(1)-adrenoceptor (AR) blocking properties, in this paper we describe the synthesis and biological characterization of the compounds designed to fully match a three-dimensional pharmacophore model for alpha(1)-AR antagonists previously developed by our research group. Accordingly, the structure of trazodone (1), identified during a database search performed by using the model as a 3D query, was chosen as the starting point for this study and modified following suggestions derived from a literature survey. In particular, the triazolopyridine moiety of trazodone was replaced with different heteroaromatic rings (such as imidazole, benzimidazole, and indole), and a pyridazin-3(2H)-one moiety was inserted into the scaffold of the new compounds to increase the overall length of the molecules and to allow for a complete fit into all the pharmacophore features. Our aim was also to study the influence of the position of both the chloro and the methoxy groups on the piperazine phenyl ring, as well as the effect of the lengthening or shortening of the polymethylene spacer linking the phenylpiperazine moiety to the terminal heterocyclic portion. Compounds obtained by such structural optimization share a 6-(imidazol-1-yl)-, 6-(benzimidazol-1-yl)-, or 6-(indol-1-yl)pyridazin-3(2H)-one as a common structural feature that represents an element of novelty in the SAR of arylpiperazine compounds acting toward alpha(1)-AR. Biological evaluation by radioligand receptor binding assays toward alpha(1)-AR, alpha(2)-AR, and 5-HT(1A) serotoninergic receptors indicated compounds characterized by very good alpha(1)-AR affinity and selectivity. Very interestingly, chemical features (such as the o-methoxyphenylpiperazinyl moiety and an alkyl spacer of three or four methylene units) that generally do not allow for 5-HT(1A)/alpha(1) selectivity led to compounds 2c and 6c with a 5-HT(1A)/alpha(1) ratio of 286 and 281, respectively. Finally, compounds with the best alpha(1)-AR affinity profile (2c, 5f, and 6c) were demonstrated to be alpha(1)-AR antagonists.

alpha(1)-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.

Synthesis and biological activity of new 1,4-benzodioxan-arylpiperazine derivatives. Further validation of a pharmacophore model for alpha(1)-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.