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 an alogs). The biological activities were assessed in vitro by examining the inhibitory effects of these agents on the electrically evoked cont ractions of the guinea pig ileum (GPI) and the mouse vas deferens (MVD ) preparations. The in vivo bioactivities were determined from the ant inociceptive activity of these agents on the 52.5 degrees C hot-plate test after spinal administration to rats with chronically placed spina l catheters. Examination of the effect of cyclization, incorporation o f retro-inverso bonds and substitutions of D- or constrained amino aci ds reveals systematic changes in the activity of these agents. There w as a significant correlation between the potency of these agents in th e hot-plate bioassay and their activity in the GPI and, to a lesser ex tent, in the MVD tests. Examination of the ability of naltrindole (a d elta selective antagonist) to reverse the drug action and the respecti ve potency on the GPI and MVD, showed that a correlation exists with a ctions 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, whe reas those with low MVD/GPI ratios act at the delta receptor in the sp inal cord. The close correlations between activity in the GPI and spin al cord suggest that the structural requirements for potency in the sm ooth muscle and in the spinal cord are essentially the same as those m u receptors that mediate nociceptive transmission.