Degradation of met-enkephalin by extracts of various regions of the human brain: effects of antipsychotics and narcotics in vitro.
Antischizophrenic drugs, reduced in a concentration-dependent fashion enkephalin degradation by the soluble and particulate fractions of the human cerebral cortex and cerebellum. The order of potency is as follows: thioridazine greater than chlorpromazine greater than fluphenazine greater than haloperidol greater than or equal to promazine with IC50 of 50, 80, 120, 200-250 micro M, respectively. Kinetic studies revealed non-competitive and competitive inhibition by thioridazine and chlorpromizine, respectively. Narcotics, were weak inhibitors of enkephalin degradation. For dl-, d-, l-methadone and l-alpha-acetylmethadol, IC50 was about 500 micro M, and 1000 micro M for heroin and morphine. It is suggested that inhibition of the degradation of endogenous morphinomimetic peptides in the CNS may be a crucial factor governing the pharmacology of some neuroleptics and other psychoactive drugs. Enkephalin-hydrolyzing activity was ubiquitous and exhibited considerable regional differences in the normal human and in Huntington's chorea brains. The rate of enkephalin degradation is generally higher in the subcortical nuclei than in the cortex and cerebellum. The highest hydrolytic activity was found in the substantia nigra, anterior thalamus, septal area, globus pallidus and caudate nucleus, in this decreasing order.
D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004723:Endorphins / Q000378:metabolism*; D004744:Enkephalin, Methionine; D004745:Enkephalins / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007700:Kinetics; D009294:Narcotics / Q000494:pharmacology*; D013881:Thioridazine / Q000494:pharmacology; D014018:Tissue Distribution
D014150:Antipsychotic Agents; D004723:Endorphins; D004745:Enkephalins; D009294:Narcotics; D004744:Enkephalin, Methionine; D013881:Thioridazine