d-ala(2)-mephe(4)-met(0)-ol-enkephalin and metkephamid

The effects of the degradation-resistant enkephalin analogs FK 33-824 and metkephamid were determined after systemic and intracerebroventricular (i.c.v.) administration in withdrawn morphine-dependent rhesus monkeys. Both peptides suppressed completely signs of 12-hr morphine deprivation, as does the prototype mu-receptor agonist morphine. The peptides were 100 and 2000 times more potent, respectively, after i.c.v. than s.c. injection. Thus, although peptidase-resistant, these compounds have restricted entrance into the central nervous system after systemic administration. The i.c.v. administration of compounds in rhesus monkeys should prove to be a valuable tool in the study of peptide ligands for opiate receptors.

Topics: Animals; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Enkephalin, Methionine; Hormones; Humans; Injections, Intraventricular; Injections, Subcutaneous; Macaca mulatta; Morphine; Morphine Dependence

FK-33,824 (Tyr-D-Ala-Gly-MePhe-Met(O)-ol) and metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-CONH2; LY 127623) are two parenterally active synthetic analogues of the endogenous morphinomimetic pentapeptide, [Met5]-enkephalin. Acute s.c. administration of each analogue raised the seizure threshold in a dose-related manner in rats challenged with flurothyl, a volatile convulsant. The anticonvulsant action was antagonized by a low dose of naloxone (0.10 mg/kg s.c.). FK-33,824 and metkephamid can therefore be classified with typical mu-receptor agonists such as morphine and etorphine in this procedure.

Topics: Animals; Anticonvulsants; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Dose-Response Relationship, Drug; Endorphins; Enkephalin, Methionine; Enkephalins; Flurothyl; Male; Naloxone; Rats; Seizures