Dermorphin (DM), an amphibian opioid heptapeptide which contains a natural D-Ala in position 2, N-terminal DM analogues and a series of dimeric DM analogues (coupled through the C-terminus) were analyzed for mu- and delta-receptor affinities on rat brain synaptosomes. Binding assays used 3H-DAGO for mu-receptors and 3HDADLE for delta-receptors (carried out in the presence of (N-Me- Phe3,D-Pro4) morphiceptin to suppress interaction with mu- receptors). Dimeric DM tetrapeptides weakly interacted with mu- receptors; in particular, the analogue with a 12 methylene unit bridge between peptide chains had poor mu- and delta-affinities and no selectivity. However, analogue with an ethylene bridge containing D-Arg2 and Sar4 had high mu-affinity, mu-selectivity, and correlated to the inhibition of gastric acid secretion. All the dimeric DM pentapeptides had very high mu-affinities, with moderate to low mu-selectivity, but correlated in a positive manner to the suppression of gastric secretion. Whereas D-Arg and Sar increased mu-affinity and selectivity in the dimeric tetrapeptides, they decreased these parameters in the pentapeptides. Dimeric DM and DM exhibited high affinity for mu-receptors and selectivity approaching DAG0 and had a positive correlation to the inhibitory effect in the gastric secretory process. As a control for the binding specificity, the (L-Ala2)DM analogue was tested: it bound to mu-receptors with an affinity 3-orders of magnitude less than DM, which is in keeping with its minimal bioactivity. Thus, these studies provide evidence that high affinity mu-receptors in brain tissue correlate in a positive manner to the inhibition of gastric acid output in stomach by the central (icv) administration of DM and selected dimeric DM analogues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES090053-01
Application #
3918772
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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