Characterization of the spinal antinociceptive activity of constrained peptidomimetic opioids.

We examined the in vitro and in vivo bioactivities of several families of peptidomimetic opioids including: constrained linear enkephalin (n = 12 analogs), dermorphin (n = 9 analogs) and morphiceptin (n = 17 analogs). The biological activities were assessed in vitro by examining the inhibitory effects of these agents on the electrically evoked contractions of the guinea pig ileum (GPI) and the mouse vas deferens (MVD) preparations. The in vivo bioactivities were determined from the antinociceptive activity of these agents on the 52.5 degrees C hot-plate test after spinal administration of rats with chronically placed spinal catheters. Examination of the effect of cyclization, incorporation of retro-inverso bonds and substitutions of D- or constrained amino acids reveals systematic changes in the activity of these agents. There was a significant correlation between the potency of these agents in the hot-plate bioassay and their activity in the GPI and, to a lesser extent, in the MVD tests. Examination of the ability of naltrindole (a delta selective antagonist) to reverse the drug action and the respective potency on the GPI and MVD, showed that a correlation exists with actions on the MVD, but not on the GPI, consistent with the likelihood that agents with high MVD/GPI ratios in vitro act at the mu sites, whereas those with low MVD/GPI ratios act at the delta receptor in the spinal cord. The close correlations between activity in the GPI and spinal cord suggest that the structural requirements for potency in the smooth muscle and in the spinal cord are essentially the same as those mu receptors that mediate nociceptive transmission.