RESUMEN
The structure-activity relationship of 2'-pyrrole, pyrazole and triazole substituted 2-(anilinomethyl)imidazolines as alpha(1) adrenergic agonists was investigated. The size and orientation of substituents, as well as the position of the heteroatoms, were found to have a profound effect on the potency and selectivity of the molecules. Potent alpha(1A) subtype selective agonists have been identified.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/síntesis química , Agonistas alfa-Adrenérgicos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
The high-throughput manual solid-phase parallel synthesis of libraries comprising thousands of discrete samples using pellicular supports (i.e. SynPhase crowns and lanterns) and a suite of novel tools and techniques is described. Key aspects of this approach include the combination of a split-split-split synthesis strategy with spatial encoding to differentiate thousands of crowns, the rapid washing and filtration of up to 48 reaction vessels in parallel, the application of an inexpensive and environmentally friendly technique to remove trifluoroacetic acid from sixteen 96-well plates in parallel, and a high-throughput method for removing cleaved crowns from reusable pin racks. Tens of thousands of discrete samples have been produced in-house using this conceptually and operationally straightforward strategy.
RESUMEN
Literature reports suggest that disruption of an interhelical salt bridge is critical for alpha(1)-adrenoceptor activation, and the basic amine found in adrenergic receptor ligands is responsible for the disruption. Novel 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of the cloned human alpha(1)-adrenoceptors in vitro, and potent, selective alpha(1A)-adrenoceptor agonists have been identified in this series. These imidazoles demonstrate similar potencies and alpha(1)-subtype selectivities as the corresponding 2-substituted imidazolines. The extremely close SAR suggests that, in spite of the large difference in basicity, these imidazoles and imidazolines may establish the same interactions to activate alpha(1)-adrenoceptors.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/farmacología , Compuestos de Anilina/química , Imidazoles/química , Imidazoles/farmacología , Éteres Fenílicos/química , Humanos , Proteínas Recombinantes/agonistas , Relación Estructura-ActividadRESUMEN
A series of 2'-alkylthio-2-(anilinomethyl)imidazolines were prepared to examine the effect of the alkyl group size, sulfur oxidation state, and phenyl ring substitution on ligand binding and agonism of alpha-adrenergic receptor subtypes alpha1a, alpha1b, alpha1d, alpha2a, and alpha2c. Binding at all receptor subtypes decreased for compounds in the sulfone oxidation state as compared to their sulfide analogues. While sulfides were generally potent, nonselective agonists, sulfones exhibited alpha1a subtype selectivity in a cell-based functional assay. Sulfone (32) was 250-7000-fold selective for alpha1a vs all other subtypes.
Asunto(s)
Agonistas alfa-Adrenérgicos/síntesis química , Imidazoles/síntesis química , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Sulfonas/síntesis química , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/farmacología , Calcio/metabolismo , Línea Celular , AMP Cíclico/biosíntesis , Fibroblastos/metabolismo , Humanos , Imidazoles/química , Imidazoles/farmacología , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
A series of 2'-heteroaryl and 2'-oxime anilinomethylimidazolines was prepared and evaluated in in vitro functional assays for cloned human alpha1A, alpha1B, and alpha1D receptor subtypes. Potent and selective alpha1A agonists have been identified in these series.
Asunto(s)
Agonistas alfa-Adrenérgicos/síntesis química , Imidazoles/farmacología , Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Línea Celular , Clonación Molecular , Compuestos Heterocíclicos , Humanos , Imidazoles/síntesis química , Imidazoles/química , Oximas , Fenilefrina/metabolismo , Unión Proteica , Ratas , Receptores Adrenérgicos alfa 1/metabolismoRESUMEN
Novel 2'-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the cloned human alpha(1)-adrenoceptors in vitro. The nature of the 2'-heteroaryl group can have significant effects on the potency, efficacy, and subtype selectivity in this series. alpha(1A) Subtype selective agonists have been identified.