Metabolism of beta-casomorphin and its derivatives in rat brain and liver homogenates.

Derivatives of opiate-like acting beta-casomorphin (beta-CM), (Tyr-Pro-Phe-Pro-Gly), were prepared by substitution of D-amino acids. The metabolism of these analogs was studied in brain and liver homogenates. Their half-lives and the metabolites resulting from their biological degradation were determined by means of the HPLC-technique. Resistance to biological degradation, which was considerably enhanced in some derivatives, was shown to depend on the position of the D-amino acids. The following substances proved to be particularly stable: D-Pro2-beta-CM, Des-Tyr-D-Pro2-beta-CM, Des-Tyr-D-Phe3-beta-CM. The resulting metabolites suggest that the activity of proline-specific peptidases is predominant in the catabolic process. The degradation pattern of beta-CM-pentapeptides produced by peptidases in the brain and liver is completely different from that of the enkephalin-pentapeptides, which are likewise protected by substitution of D-stereoisomers for certain L-amino acids. The different degradation kinetics of beta-CM-pentapeptides in neuronal and non-neuronal tissue homogenates (liver) reflect the variation in activity of certain peptidases. Considering the half-lives that we have estimated, we suggest which of the peptides tested has a high resistance against biological degradation in vivo.