RESUMEN
A number of analogues of the recently disclosed analgesic dipeptide 2,6-dimethyl-L-tyrosyl-D-alanine-phenylpropylamide (SC-39566, 2) were prepared. These analogues contained oxymethylene, aminomethylene, ketomethylene, bismethylene, and trans double bond (including vinyl fluoride) isosteric replacements for the amide bond between the D-alanine and phenylpropylamine units in 2. These compounds were tested in opioid binding assays and in the mouse writhing assay for analgesic activity. Though not as potent as 2, the oxymethylene, and trans double bond isosteres showed analgesic activity. The aminomethylene analogues also showed binding activity in subnanomolar concentrations at the mu receptor. The amide bond between 2,6-dimethyl-L-tyrosine and D-alanine units seems to be critical for opioid activity.
Asunto(s)
Analgésicos Opioides/síntesis química , Dipéptidos/síntesis química , Receptores Opioides/metabolismo , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Animales , Encéfalo/metabolismo , Dipéptidos/metabolismo , Dipéptidos/farmacología , Técnicas In Vitro , Masculino , Ratones , Dimensión del Dolor/métodos , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and biological evaluation of a series of alpha, alpha-bis[(dialkylamino)alkyl]phenylacetamides, 2, are presented. These compounds are structurally related to the antiarrhythmic agent disopyramide (1) and in many cases were found to possess greater antiarrhythmic activity in coronary ligated dogs. Within this series of compounds, a separation of the antiarrhythmic properties from the unwanted cardiac depressant side effects observed with the parent compound, 7, was also often attained. A discussion of the structure-activity relationships within the series is presented; this work has culminated in the identidiction of compound 35 (disobutamide) as a candidate for clinical evaluation as an antiarrhythmic agent in man.
Asunto(s)
Acetamidas/síntesis química , Antiarrítmicos/síntesis química , Acetamidas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Vasos Coronarios/fisiología , Perros , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Ligadura , Relación Estructura-ActividadRESUMEN
The extent of plasma binding, the partition coefficient, and the pKb of 13 disopyramide derivatives were determined. The structural variation on the diisopropylaminoethyl group of disopyramide molecules influenced these physical parameters to varying degrees. Results demonstrated that the extent of interaction between drugs and human plasma was a linear function of their lipophilicity and inversely proportional to the magnitude of the pKb value.