RESUMEN
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.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Flavonoides/química , Piperazinas/síntesis química , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Corteza Cerebral/metabolismo , Flavonas , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Piperazinas/química , Piperazinas/farmacología , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Receptores de Serotonina 5-HT1/efectos de los fármacos , Receptores de Serotonina 5-HT1/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Piperazinas/síntesis química , Piridazinas/síntesis química , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Sitios de Unión , Unión Competitiva , Corteza Cerebral/metabolismo , Técnicas In Vitro , Ligandos , Piperazinas/química , Piperazinas/farmacología , Piridazinas/química , Piridazinas/farmacología , Ratas , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/farmacología , Piridazinas/síntesis química , Piridazinas/farmacología , Fenómenos Químicos , Química Física , Ciclización , Ensayo de Unión Radioligante , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1RESUMEN
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.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Imidazoles/síntesis química , Piperazinas/síntesis química , Piridazinas/síntesis química , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Corteza Cerebral/metabolismo , Imidazoles/química , Imidazoles/farmacología , Técnicas In Vitro , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacología , Piridazinas/química , Piridazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Relación Estructura-ActividadRESUMEN
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.