Delta opioid receptor selective ligands; DPLPE-deltorphin chimeric peptide analogues†

Further efforts to correlate the topography of the bioactive structures of DPDPE and the deltorphins, two δ-opioid receptor active peptide families, are reported. A number of DPLPE-deltorphin chimeric peptides have been synthesized in which the C-terminal dipeptide δ-address of the deltorphins (-Val-GlyNH₂, -Nle-GlyNH₂) have been linked to the highly δ-opioid selective cyclic peptides DPDPE or DPLPE. These studies demonstrate that a major structural feature determining high potency of hybrid analogues is the chirality of the amino acid residue in position 5. The radioligand binding assays have revealed a decrease in potency (compared to DPDPE) at §-receptors when the C-terminal dipeptides were added to DPDPE. On the other hand, chimeric peptides of DPLPE with these same C-terminal dipeptides retained high δ-selectivity and affinity. Similar results were obtained using the mouse vas deferens (MVD) and guinea pig ileum (GPI) bioassays. The importance of the hydrophilicity of amino acids in positions 2 and 5 for δ-selectivity is consistent with the previous finding for DPLPE and DPDPE. On the other hand, the replacement of phenylalanine-4 with p-chlorophenylalanine-4 did not increase δ-selectivity as in DPDPE. These findings suggest that the δ-receptor interacts with hybridized enkephalins and deltorphins somewhat differently than with DPDPE.     

Oral florid papillomatosis in the course of lichen planus

The causal relationship between oral florid papillomatosis and lichen planus is discussed in the light of the literature and a case report.     

Lipid membrane permeability of modified c[D-Pen2, D-pen5]enkephalin peptides

Permeability coefficients of a series of analogues of a potent opioid peptide, c[D-Pen², D-Pen⁵]enkephalin, were measured in a model membrane system. The analogues included hydrophobic amino acid substitutions on position 3. Liposomes of a mixed composition consisting of zwitterionic lipids and cholesterol served as the model membranes. The obtained permeability coefficients range between 0.38 × 10^?12 and 2.9 × l0^?12 cm/s. These data were correlated with the hydrophobicity scale of Nozaki and Tanford (J. Biol. Chem. 246, 1971, 2211-2217) (correlation coefficient = 0.9933) and with determinations of lipid order perturbation by differential scanning calorimetry (correlation coefficient = -0.9779). The reasonably good correlation obtained within the family of analogues substituted on position 3 (Gly, Ala, Leu, Phe) indicates that changes in permeabilities are primarily related to increases in the partition coefficient of the peptide. However, Phe residue added on the N-terminal end of the peptide (position 0) does not appear to follow the observed trend, showing stronger lipid perturbation and lower permeability compared to the Phe³ analog. This observation demonstrates that each class of peptide modifications requires a new basis of permeability analysis and predictions. © Munksgaard 1996.     

Reduced-dose rocuronium for day-case tonsillectomy in children where volatile anaesthetics are not used: operating room time saving

Objectives: Mivacurium, rocuronium, and vecuronium are neuromuscular blocking agents (NMB) commonly used in pediatric day‐case anesthesia. Mivacurium is the most appropriate NMB for short surgical procedures where NMB drugs were required but is not available in all countries. Aim: We evaluated the operating room time minimization after reduced‐dose rocuronium (0.45 mg·kg^?1) during elective day‐case tonsillectomy in children. Methods/Materials: One hundred and five children (6–9 years, ASA I/II status) scheduled for day‐case tonsillectomy were included in prospective, double blind clinical study. Children were randomly divided in three equal groups. All children were premedicated (midazolam 0.25 mg·kg^?1 orally, EMLA). Anesthesia was induced (2.5 mg·kg^?1) and maintained (0.1 mg·kg^?1·min^?2) by propofol and alfentanil (0.0015 mg·kg^?1·min^?1) and supplemented by inhalation mixture of 50% of O2/Air. Neuromuscular block was achieved by vecuronium (0.1 mg·kg^?1) (V) or rocuronium in standard (0.6 mg·kg^?1) (R) or reduced dose (0.45 mg·kg^?1) (LD). Neuromuscular transmission was monitored by acceleromyography. Time analysis of NMB drugs action was performed. Results: Time difference from the end of tonsillectomy to T90 neuromuscular block recovery was significantly shorter in LD Group (7.3 ± 0.41 min), (V = 15.9 ± 1.06, R = 16.0 ± 1.7 min) (P = 0.0011). The onset time of neuromuscular block was prolonged in LD Group (LD=3.1 ± 0.4, R = 1.3 ± 0.4, V = 2.2 ± 0.2 min) (P = 0.0039) without changing the intubating conditions. The maximum operation room time saving per each tonsillectomy was 37% in LD Group (Group V 21%, Group R 17%) (P = 0.0001). Low incidence of postoperative nausea and vomiting (PONV) 3–6% (0.4577) and good visual analog scale (VAS) score (≤2) (0.5969) were found in all study groups 12 h after surgery. Conclusions: Reduced‐dose rocuronium in addition with propofol and alfentanil in children where volatile anesthetics are not used effectively saves the operating room time during short elective surgical procedures, avoids delays in patient recovery, allows high level of acceptable intubating conditions, and improves the optimal surgical work. Low incidences of PONV as VAS score may achieved successfully.     

Immunosuppressive analogues of hexapeptide Tyr-Val-Pro-Leu-Phe-Pro,an immune system stimulant

It was found that substitution of Val² and/or Leu⁴ residue in a hexapeptide Tyr-Val-Pro-Leu-Phe-Pro (I) transforms this peptide immunostimulant into analogues possessing the immunosuppressor activity – Tyr-Gly-Pro-Leu-Phe-Pro (II), Tyr-Val-Pro-Gly-Phe-Pro (III), and Tyr-Gly-Pro-Gly-Phe-Pro (IV). Biological effects of peptides I-IV were studied using PFC (plaque forming cell) test, GvH (graft vs host) reaction in mice, and ARFC (autologous rosette forming cell) test. The strongest immunosuppressor activity was observed for III – in this case the immunosuppressor effect was observed even in PFC test in vitro in which II and IV showed no such activity. These results suggest that simultaneous presence of both Val² and Leu⁴ residues is necessary for the generation of immunostimulation. The CD study of I-IV in methanol solution suggests that the conformational preferences of II-IV change towards stabilization of the β-turn structure, whereas in the case of I the γ-turn on Leu⁴ and cis orientation of the Pro³ carbonyl (distorted β-turn of type I) was found (1) as the preferred conformation. Competition in biological effects observed for I and III in PFC in vitro test suggests that these analogues may interact with the same cellular receptor. Drastic changes in the activity which accompany changes in the sequence are discussed in the terms of our stereochemical hypothesis (1).