Identification of β-endorphin-(6-17) as the principal metabolite of des-tyrosine-γ-endorphin (DTγE) in vitro and assessment of its activity in neurotransmitter receptor binding assays

Des-tyrosine-γ-endorphin (β-endorphin-(2-17); DTγE) 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 DTγE may exert its selective, neuroleptic-like activity through an active metabolite. Accordingly, DTγE was incubated at 37°C in a whole rat brain homogenate of neutral pH after which samples were prepared for HPLC analysis. The major, heat-stable metabolite of DTγE was identified as the clinically active, β-endorphin related fragment, β-endorphin-(6-17). The β-endorphin sequences 4-17, 5-17, 10-17, 12-17 and 2-16 were also present but in minor amounts. Identical results were obtained studying DTγE metabolism using rat striatal tissue slices. Neurotransmitter receptor binding experiments showed that β-endorphin-(6-17) was inactive at central dopaminergic, serotonergic, muscarinic, benzodiazepine and opiate receptors measured in vitro. Thus, like DTγE, β-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 DTγE and β-endorphin-(6-17) 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.