RESUMO
This study characterized the prototypic "minimum structure" enkephalin SC-39566 [2,6-dimethyl-L-tyrosinyl-D-alanine-(3-phenyl-1-propyl)-amide hydrochloride]. SC-39566 bound with highest affinity to mu opioid receptors (Ki, 0.13 nM), as well as to delta (Ki, 4.0 nM) opioid receptors in the rat brain, and with much lower affinity to kappa opioid receptors (Ki, 83.8 nM) in the guinea pig brain. In the mouse, SC-39566 inhibited phenylbenzoquinone-induced writhing and increased tail-flick and hot-plate latencies in a dose-dependent manner after either s.c. or p.o. (i.g.; intragastrical) administration. This antinociception was antagonized by the opioid antagonist naloxone, but not by alpha adrenergic, serotonergic, histaminergic, muscarinic cholinergic or dopaminergic receptor antagonists. In the rat, SC-39566 dose-dependently inhibited acetic-acid-induced writhing after s.c. or i.g. administration and increased response latencies in the tail-flick and hot-plate test after s.c. or intrathecal (i.t.) administration. The increase in tail-flick latency produced by s.c. SC-39566 in the rat was antagonized by s.c. naloxone with an apparent pA2 value of 7.9. Pretreatment with naltrindole, a delta opioid receptor antagonist, increased the ED50 of SC-39566 by only 1.7-fold. In addition, the increase in tail-flick latency produced by i.t. SC-39566 was not antagonized by i.t. administration of naltrindole or nor-binaltorphimine, a kappa receptor antagonist. These data suggest that the antinociceptive activity of SC-39566 is mediated predominantly by mu opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Analgésicos/farmacologia , Dipeptídeos/farmacologia , Administração Oral , Animais , Dipeptídeos/administração & dosagem , Cobaias , Injeções Espinhais , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides kappa/efeitos dos fármacos , Fatores de TempoRESUMO
Analogues of bradykinin were synthesized containing single substitutions by N alpha-methyl amino acids in the 1, 4, 5, 5, and 9 positions. [MeArg]Bradykinin possessed 60% of the muscle-contracting activity of the parent compound in a guinea pig ileum assay. The other analogues were very weak agonists (less than 2%) and, disappointingly, failed to show blocking activity except at very high doses.
Assuntos
Bradicinina/análogos & derivados , Animais , Bradicinina/antagonistas & inibidores , Bradicinina/síntese química , Bradicinina/farmacologia , Cobaias , Técnicas In Vitro , Metilação , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacosRESUMO
The dipeptide ester L-aspartyl-L-phenylalanine methyl ester (APM) has been found to have a remarkably clean, sucrose-like taste with no off flavor and a potency 150-200 times sucrose. Subsequent work has shown that many alpha-amides of L-aspartic acid are sweet. Some results of stability studies and a taste panel evaluation of APM are reported.