NEUROPEPTIDES: MOLECULAR MECHANISM OF ACTION

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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.