RESUMEN
The asymmetric unit of the title compound, C(17)H(13)N, contains two independent butterfly-shaped mol-ecules. The seven-membered azepine rings both adopt a boat conformation. The dihedral angles between the benzene rings in the two mol-ecules are 46.95â (11) and 52.21â (11)°.
RESUMEN
In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Indoles/síntesis química , Prazosina/análogos & derivados , Hiperplasia Prostática/tratamiento farmacológico , Quinazolinas/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Línea Celular , Perros , Doxazosina/farmacología , Diseño de Fármacos , Humanos , Indicadores y Reactivos , Indoles/química , Indoles/farmacología , Isoindoles , Células L , Masculino , Ratones , Modelos Moleculares , Conformación Molecular , Prazosina/farmacología , Próstata/metabolismo , Quinazolinas/química , Quinazolinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Adrenérgicos alfa 1 , Proteínas Recombinantes/antagonistas & inhibidores , Bazo/metabolismo , Relación Estructura-Actividad , Conducto Deferente/metabolismoRESUMEN
In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Indoles/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Línea Celular , Perros , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacología , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Masculino , Presión , Hiperplasia Prostática/tratamiento farmacológico , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas SHR , Estereoisomerismo , Relación Estructura-Actividad , Uretra/efectos de los fármacos , Uretra/fisiologíaAsunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Indoles/síntesis química , Hiperplasia Prostática/tratamiento farmacológico , Pirimidinonas/síntesis química , Antagonistas Adrenérgicos alfa/uso terapéutico , Animales , Perros , Humanos , Indoles/uso terapéutico , Isoindoles , Masculino , Modelos Químicos , Prazosina/análogos & derivados , Prazosina/uso terapéutico , Pirimidinonas/uso terapéutico , Ratas , Receptores Adrenérgicos alfa 1 , Sulfonamidas/uso terapéutico , TamsulosinaRESUMEN
The inducible human cationic amino acid transporter hCAT-2B was expressed in Xenopus laevis oocytes, and this system was used to test the effect of several NO synthase (NOS) inhibitors and/or L-arginine analogues on L-arginine transport by this y+ carrier. L-NG-Methyl-L-arginine (L-NMA), asymmetrical L-NG, NG-dimethyl-L-arginine (L-ADMA), L-N5-(1-iminoethyl)-ornithine (L-NIO), L-NG-nitro-L-arginine (L-NNA), and L-NG-nitro-L-arginine methyl ester (L-NAME) all inhibited the inducible NOS II extracted from RAW 264.7 macrophages induced with bacterial lipopolysaccharide. L-NMA, L-ADMA, and L-NIO also competed with L-arginine for transport by hCAT-2B, whereas L-NNA and L-NAME did not. The two L-arginine analogues, symmetrical NG, NG-dimethyl-L-arginine (L-SDMA) and alpha-amino-delta-isothioureidovaleric acid (AITV), as well as L-lysine, did not block enzymatic activity of NOS II, but did compete for L-arginine transport mediated by hCAT-2B. L-Lysine and L-SDMA were transported efficiently by hCAT-2B and exchanged against intracellular L-arginine, resulting in an L-arginine depletion of the cells. AITV was a much poorer substrate of hCAT-2B and had only little effect on intracellular L-arginine concentrations. These data indicate that substrate recognition differs markedly between the inducible L-arginine transporter hCAT-2B and the inducible NOS II, with different L-arginine analogues having affinity to only one or both of these proteins.
Asunto(s)
Arginina/análogos & derivados , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/metabolismo , Sistemas de Transporte de Aminoácidos Básicos , Animales , Arginina/metabolismo , Arginina/farmacología , Transporte Biológico , Línea Celular , Inhibidores Enzimáticos , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1 , Humanos , Lisina/farmacología , Ratones , Proteínas de Transporte de Monosacáridos/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Oocitos/metabolismo , Ratas , Xenopus laevisRESUMEN
A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were much more potent than compounds with an alkyl group (R) on the heterocyclic ring. The corresponding pyridine, pyridazine, pyrazine, and 1,2,4-triazine carboxylic acids also showed potent in vitro angiotensin II antagonism. The pyridine (W, X, Y = CH, Z = COOH, R' = n-C3H7) demonstrated potent in vitro activity (pA2 = 10.10, rabbit aorta, and Ki = 0.61 nM, receptor binding in rat liver) as well as exceptional oral antihypertensive activity and bioavailability. Any nonacidic replacement for the carboxylic acid was detrimental for activity.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Niacina/análogos & derivados , Ácidos Nicotínicos/química , Tetrazoles/química , Angiotensina II/farmacología , Antagonistas de Receptores de Angiotensina , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Aorta/fisiología , Disponibilidad Biológica , Radioisótopos de Yodo , Hígado/metabolismo , Masculino , Contracción Muscular/efectos de los fármacos , Niacina/química , Niacina/farmacología , Ácidos Nicotínicos/farmacocinética , Ácidos Nicotínicos/farmacología , Conejos , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Receptores de Angiotensina/metabolismo , Tetrazoles/farmacocinética , Tetrazoles/farmacologíaRESUMEN
The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Imidazoles/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Agonistas alfa-Adrenérgicos/síntesis química , Animales , Perros , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/síntesis química , Técnicas In Vitro , Masculino , Conformación Molecular , Conejos , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
A previous report of the adrenergic selectivity of 2- and 6-fluoronorepinephrine prompted us to formulate a hypothesis that accounted for this selectivity on the basis of a conformational preference induced by electrostatic repulsion between the aromatic fluorine atom and the side-chain hydroxyl group. A series of nitrogen-substituted catechol (aminomethyl)benzocyclobutenes, indanes, tetralins, and benzocycloheptenes were prepared, and when their radioligand binding affinities were determined, it was found that the overall pattern of binding affinity results supported the electrostatic repulsion hypothesis. The radioligand binding assay also revealed several highly alpha 2 selective adrenergic agents among these compounds, with the binding selectivity maximizing for compounds having nitrogen substituted with a group no larger than methyl and having a five-membered carbocyclic ring (i.e., 16, 17, and 19).