RESUMEN
New, potent, and selective histamine H3 receptor antagonists have been synthesized by employing the use of (1) an appropriately positioned nonpolar acetylene spacer group, (2) either a two-carbon straight chain linker or a conformationally restricting trans-cyclopropane ring between the C-4 position of an imidazole headgroup and the acetylene spacer, and (3) a Topliss operational scheme for side-chain substitution for optimizing the hydrophobic domain. Compounds 9-18 are examples synthesized with the two-carbon straight chain linker, whereas 26-31 are analogues prepared by incorporation of the trans-(+/-)-cyclopropane at the C-4 position of an imidazole headgroup. Synthesis of both the (1R,2R)- and (1S, 2S)-cyclopropyl enantiomers of the most potent racemic compound 31 (Ki = 0.33 +/- 0.13 nM) demonstrated a stereopreference in H3 receptor binding affinity for the (1R,2R) enantiomer 32 (Ki = 0.18 +/- 0.04 nM) versus the (1S,2S) enantiomer 33 (Ki = 5.3 +/- 0.5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)imidazole (32) is one of the most potent histamine H3 receptor antagonists reported to date.
Asunto(s)
Acetileno/química , Antagonistas de los Receptores Histamínicos/síntesis química , Imidazoles/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Animales , Corteza Cerebral/metabolismo , Diseño de Fármacos , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Técnicas In Vitro , Ratas , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A sensitive and versatile analytical method utilizing high-performance liquid chromatography (HPLC) and precolumn derivatization of 1H-4-substituted imidazole compounds is described. A HPLC method using 4-dimethylaminoazobenzene-4'-sulfonyl chloride (dabsyl chloride) and ultraviolet (UV) detection was developed for the analysis of histamine (HA) H3-selective compounds in human plasma, rat plasma, or homogenized rat cortical tissue. The average intra- and inter-assay variability, over a range of 10 to 0.01 microg/ml, was determined to be acceptable. The lower limit of detection for the dabsylated ligands was estimated to be <1.0 ng/ml while the lower limit of quantitation (LLOQ) was determined to be 10 ng/ml of conjugate. This assay has demonstrated it's suitability for the sensitive quantitation of several structurally diverse 1H-4-substituted imidazole HA H3-receptor antagonists in biological matrices for pharmacokinetic and biodistribution studies.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Antagonistas de los Receptores Histamínicos/análisis , Imidazoles/análisis , Receptores Histamínicos H3 , p-Dimetilaminoazobenceno/análogos & derivados , Animales , Corteza Cerebral/química , Fenómenos Químicos , Química Física , Estabilidad de Medicamentos , Antagonistas de los Receptores Histamínicos/sangre , Humanos , Imidazoles/sangre , Masculino , Control de Calidad , Ratas , Ratas Sprague-Dawley , Sensibilidad y EspecificidadAsunto(s)
Corazón/diagnóstico por imagen , Compuestos Organometálicos/farmacocinética , Compuestos de Organotecnecio , Fosfinas/farmacocinética , Tecnecio , Animales , Gatos , Cricetinae , Perros , Cobayas , Haplorrinos , Humanos , Papio , Conejos , Cintigrafía , Ratas , Especificidad de la Especie , Porcinos , Distribución TisularRESUMEN
Techniques have been developed which allow HPLC (high performance liquid chromatography) to be used for the quantitative determination of [99mTc]pertechnetate in radiopharmaceuticals and biological samples. An instrumental technique accounts for 99mTc species which do not elute from the HPLC column, while a chemical technique obviates interferences caused by Sn(II). These two techniques are incorporated into an anion exchange HPLC procedure which is applied to the determination of [99mTc]pertechnetate in 99mTc-diphosphonate radiopharmaceuticals and biological samples.