morphinans 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

Topics: Animals; Benzomorphans; Binding Sites; Brain; Cattle; Dihydromorphine; Endorphins; Etorphine; In Vitro Techniques; Morphinans; Rats; Receptors, Opioid; Retina; Tritium

The simultaneous addition of [D-Ala2, D-Leu5]-enkephalin and morphiceptin at concentrations at which 98% of enkephalin (delta) and morphine (mu) receptors are occupied only partially inhibits the binding of [3H]diprenorphine to rat brain membranes. These conditions, furthermore, do not affect the curves for displacement of [3H]diprenorphine binding by unlabeled diprenorphine. These data suggest that [3H]diprenorphine binds to a third subtype of opiate binding site, which has high affinity for diprenorphine but very low affinity for mu and delta agonists. The [3H]-diprenorphine binding observed in the presence of morphiceptin and [D-Ala2, D-Leu5]enkephalin exhibits high affinity for several benzomorphan drugs in the chemical family of 6,7-benzomorphan (e.g., cyclazocine, ethylketocyclazocine, SKF 10047, UM 1072, oxilorphan, etc). Because of its selectivity for most benzomorphan drugs, this putative receptor site is tentatively referred to as a benzomorphan binding site. Its regional distribution in rat brain is similar to that of morphine (mu) receptors but differs from that for enkephalin (delta) receptors. The content of benzomorphan binding sites in rat brain is only one-half to one-third that of morphine receptors. The relative affinities of various opioids to morphine enkephalin, and benzomorphan binding sites are also described.

Topics: Animals; Benzomorphans; Binding, Competitive; Brain; Brain Mapping; Diprenorphine; Endorphins; Enkephalins; Morphinans; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu; Structure-Activity Relationship