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.