RESUMEN
Using appropriate protection and deprotection sequence novel hydroxyacyl chains of the type CO(CH2)nOH are synthesized and are utilized to develop new analogues of forskolin. Several compounds showed good positive inotropic activity. Compound 12 is almost 10 times more active than forskolin (EC50 = 0.002 microgram/ml).].
Asunto(s)
Colforsina/análogos & derivados , Colforsina/síntesis química , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Acilación , Animales , Presión Sanguínea/efectos de los fármacos , Colforsina/química , Colforsina/farmacología , Cobayas , Corazón/fisiología , Atrios Cardíacos , Hidroxilación , Técnicas In Vitro , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
8,13-Epoxy-6 beta-(piperidinoacetoxy)-1 alpha,7 beta, 9 alpha-trihydroxy-labd -14en-11-one (HL 706, CAS 114376-11-3) is a water soluble derivative of forskolin with positive inotropic and vasodilating properties. In both in vitro and in vivo preparations, it exhibited significant positive inotropic activity with concomitant increase in heart rate and decrease in mean blood pressure. Though its potency is lower than that of forskolin, its duration of action is more prolonged. In conscious dog experiments, HL 706, administered orally, also showed a dose related increase in LV dP/dtmax. A significant reversal of cardiac failure was attained in anaesthetised dogs subjected to propranolol induced cardiac insufficiency. HL 706, like forskolin increased cAMP by virtue of its adenylate cyclase stimulant activity. Through increase in cAMP it also exhibited non-specific smooth muscle relaxant activity in isolated vascular and ileal preparations. Its therapeutic ratio is quite favourable.
Asunto(s)
Cardiotónicos/farmacología , Colforsina/análogos & derivados , Adenosina Difosfato/farmacología , Anestesia , Animales , Cardiotónicos/toxicidad , Gatos , Colforsina/farmacología , Cricetinae , Perros , Electrocardiografía , Femenino , Cobayas , Corazón/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Íleon/efectos de los fármacos , Técnicas In Vitro , Infusiones Intravenosas , Isoproterenol/farmacología , Masculino , Mesocricetus , Músculo Liso/efectos de los fármacos , Daño por Reperfusión Miocárdica/fisiopatología , Músculos Papilares/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Propranolol/farmacología , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
Using the novel lead from hydroxy acetyl substituted forskolin analogues, such as 7 beta-hydroxyacetyl-7 beta-deacetyl forskolin or 6 beta-hydroxyacetyl forskolin, a number of water soluble omega-amino acyl derivatives were synthesized. Two such compounds 6 and 18 showed better in vitro activity but failed to show in vivo activity.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Colforsina/análogos & derivados , Colforsina/síntesis química , Contracción Miocárdica/efectos de los fármacos , Acetilación , Animales , Gatos , Colforsina/química , Colforsina/farmacología , Cobayas , Corazón/efectos de los fármacos , Corazón/fisiología , Atrios Cardíacos , Hidroxilación , Técnicas In Vitro , Indicadores y Reactivos , Contracción Miocárdica/fisiología , Solubilidad , Relación Estructura-Actividad , AguaRESUMEN
Ester analogues of methyl-2-(4-(2-piperidinoethoxy)benzoyl)-benzoate hydrochloride (pitofenone) (2) were prepared with an aim to find a more potent and metabolically stable antispasmodic compound. The compounds were evaluated for their in vitro and in vivo antispasmodic activity, and stability to in vitro enzymatic hydrolysis. Of the compounds synthesised, HL 752 (21) showed the most potent and long-lasting antispasmodic activity and was selected as the candidate for clinical development.