naltrindole and morphiceptin

A chimeric opioid peptide (MCRT, YPFPFRTic-NH(2)) was here designed and synthesized. This peptide was based on morphiceptin (YPFP-NH(2)) and a neuropeptide FF (NPFF) derivative (PFRTic-NH(2)) sharing one proline. This peptide is intended to produce potent analgesia. MCRT was found to induce analgesic activity in a dose- and time-dependent manner, as indicated by a tail flick latency test in mice to which it had been intracerebroventricularly administered (5-60 min, 0.025-2.5 nmol/kg (0.5-50 pmol per mouse), ED(50)=1.49 nmol/kg). At 2.5nmol/kg, MCRT showed significantly higher levels of analgesic activity than morphiceptin or PFR(Tic)amide at 2500 nmol/kg. Naltrindole and cyprodime were found to partially but significantly inhibit this analgesic activity, but naloxone blocked it completely. The kappa opioid receptor antagonist nor-BNI was found to slightly inhibit MCRT and morphiceptin. Pre-injection of BIBP3226 and co-administration of NPFF and MCRT showed that NPFF receptors were involved in the analgesia of MCRT. BIBP3226 was found to weaken the analgesic effects of MCRT, but BIBP3226 could not block the analgesic effects of PFR(Tic)amide. Overall, MCRT was found to have stronger analgesic activity than morphiceptin or PFR(Tic)amide when interacting with mixed μ/δ opioid receptor interactions. MCRT also showed partial interaction with NPFF receptors.

Topics: Analgesia; Analgesics, Opioid; Animals; Arginine; Dose-Response Relationship, Drug; Endorphins; Guinea Pigs; Male; Mice; Morphinans; Naloxone; Naltrexone; Neuropeptides; Opioid Peptides; Proline; Receptors, Neuropeptide; Tetrahydroisoquinolines; Time Factors

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.

Topics: Amino Acid Sequence; Analgesia; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Endorphins; Enkephalins; Injections, Spinal; Male; Mice; Molecular Sequence Data; Muscle, Smooth; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Oligopeptides; Opioid Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord; Structure-Activity Relationship; Vas Deferens