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

Abstract

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.