Identification of beta-endorphin-6(16-17) as the principal metabolite of des-tyrosin-gamma-endorphin (DTgammaE) in vitro and assessment of its activity in neurotransmitter receptor binding assays.
Des-tyrosine-gamma-endorphin (beta-endorphin-(2-17); DTgamma E) lacks direct in vitro activity at dopaminergic receptors, but does inhibit in vivo [3H]spiperone binding in various rat brain areas. The principal objective of these studies was to test the hypothesis that DTgammaE may exert its selective, neuroleptic-like activity through an active metabolite. Accordingly, DTgammaE was incubated at 37 degrees C in a whole rat brain homogenate of neutral pH after which samples were prepared for HPLC analysis. The major, heat-stable metabolite of DTgammaE was identified as the clinically active, beta-endorphin related fragment, beta-endorphine-(6-17). The beta-endorphin sequences 4-17, 5-17, l0-17, 12-17 and 2-16 were also present but in minor amounts. Identical results were obtained studying DTgammaE metabolism using rat striatal tissue slices. Neurotransmitter receptor binding experiments showed that beta-endorphin-(6-17) was inactive at central dopaminergic, serotonergic, muscarinic, benzodiazepine and opiate receptors measured in vitro. Thus, like DTgammaE, beta-endorphin-(6-17) differs from classical neuroleptics in that it does not inhibit in vitro [3H]spiperone binding in the corpus striatum, frontal cortex or mesolimbic areas of the rat brain. It may be that DTgammaE and beta-endorphine-(66-17) exert their selective neuroleptic-like activity through an indirect inhibition of central dopaminergic activity, possibly in combination with an in vivo antagonism of the postsynaptic dopamine receptor.
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004723:Endorphins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009116:Muscarine / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011955:Receptors, Drug / Q000378:metabolism*; D011963:Receptors, GABA-A; D011957:Receptors, Opioid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D001615:beta-Endorphin
D004723:Endorphins; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D011957:Receptors, Opioid; D012701:Serotonin; D001615:beta-Endorphin; C018903:gamma-endorphin, des-Tyr(1)-; D009116:Muscarine; D004298:Dopamine