SYNTHESIS AND BIOLOGICAL PROPERTIES OF GAMMA-GLUTAMYL-DERMORPHIN, A PRODRUG

The possibility of using the gamma-glutamyl-transpeptidase system for transformation of inactive propeptide, gamma-glutamyl-neuropeptides in to active neuropeptides has been tested on dermorphin and its gamma-gl utamyl analogue. Gamma-glutamyl-dermorphin 2 showed little affinity fo r opioid receptors. Nonetheless, systemic (intraperitoneal (i.p.), or intravenous (i.v.)) application of this compound induced significant a ntinociceptive effects, although ten to twenty-fold higher doses were required compared to the parent dermorphin 1. On the other hand, the a nalogue 2 showed high, antinociceptive activity when injected intrathe cally (i.t.). When compared to dermorphin, 2 was one third as potent, but did show a significant prolonged duration of the effect. These res ults suggest that in the periphery, the peptidase metabolism which res ults in degradation of bioactivity, is offset by gammaglutamyl transpe ptidase (GGTP) activity that liberates bioactive peptide 2. On the oth er hand, in the central nervous system, the activity of gamma-glutamyl -transpeptidase system seems to be more effective than other peptidase systems, resulting in formation of active peptide 2 in a significant amount. These data suggests that gamma-glutamyl analogues of neuropept ides can be considered as potential prodrugs, especially for synthetic analogues which themselves are resistant to peptidase action.