Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To avoid the confounding effect of metabolic degradation, the stable mu-opioid peptide agonist [D-Arg2,Lys4]-dermorphin analogue (DALDA) was used to quantitate blood-brain barrier (BBB) permeability by intravenous injection and internal carotid artery perfusion techniques. With intravenous injection, the BBB permeability-surface area products for [3H]DALDA (0.84 +/- 0.13 microliters.min-1.g-1) and [14C]sucrose (0.39 +/- 0.05 microliters.min-1.g-1) correlated with the lipid solubility of the two molecules: the 1-octanol-Ringer partition coefficient for DALDA was approximately 2 log orders greater than that for sucrose. The brain delivery of [3H]DALDA at 30 min after intravenous administration was 0.019 +/- 0.002% of the injected dose per gram, and analgesia was induced with a 5-mg/kg dose administered systemically. In contrast to the result after intravenous injection, the BBB permeability-surface area product for DALDA estimated with the internal carotid artery perfusion technique was manyfold greater. This was due to nonspecific absorption of the peptide into the cerebral microvasculature, which precluded use of the capillary depletion technique to study transcytosis through the BBB after internal carotid artery perfusion. The present studies show that the brain delivery of a metabolically stable peptide, such as DALDA, is comparable to that for sucrose, correlates with lipid solubility, and is mediated by a nonsaturable mechanism, probably free diffusion.
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PMID:Blood-brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue. 804

Delivery through the blood-brain barrier of opioid peptide-based therapeutic agents may be achieved with the use of conjugation of avidin and blood-brain barrier transport vectors. However, this drug delivery strategy requires that 1) the peptide is monobiotinylated and 2) the peptide is biologically active after cleavage of a disulfide linker and peptide release from the avidin-vector conjugate. Whether these criteria may be successfully fulfilled was examined in the present studies. The highly mu receptor-specific dermorphin analog, Tyr-D-Arg-Phe-Lys-NH2 (DALDA), was selectively monobiotinylated at the epsilon-NH2 group of Lys4 with the cleavable biotin linker, sulfosuccinimidyl-2-(biotinamidoethyl) 1,3'-dithioproprionate to obtain biotinylated DALDA (bio-DALDA). The N-terminal alpha-NH2 group of the peptide was protected during biotinylation with the N-9-fluorenylmethoxycarbonyl group. Cleavage of the disulfide bridge yielded the desbiotinylated derivative, desbio-DALDA. The identity of these peptides was verified by secondary ion mass spectrometry. In receptor binding assays with 3H-Tyr-D-Ala-Gly-Phe-(N-Me)-Gly-ol, the Kis of DALDA, bio-DALDA and desbio-DALDA for mu opioid receptors were determined to be 2.3 +/- 0.4, 6.5 +/- 1.1 and 4.0 +/- 0.9 nM, respectively. Binding of bio-DALDA to avidin resulted in a Ki of 14.5 +/- 2.4 nM. The i.c.v. administration of DALDA and desbio-DALDA induced potent and long-lasting analgesia in the rat tail-flick assay. It was found that 1 microgram of DALDA was equipotent to 3 micrograms of desbio-DALDA and 20 micrograms of morphine. The analgesic effect could be blocked by naloxone pretreatment. In conclusion, these studies 1) described methods for the preparation of a biologically active monobiotinylated mu opioid receptor-specific ligand and 2) demonstrated the advantages of using cleavable biotinylation of opioid peptides because the affinity of desbio-DALDA for the receptor approximated the affinity of DALDA and had a 3- to 4-fold higher affinity than did the bio-DALDA-avidin complex.
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PMID:Synthesis and bioactivity of monobiotinylated DALDA: a mu-specific opioid peptide designed for targeted brain delivery. 811 91

The tetrapeptide DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) is a polar and selective mu agonist showing poor penetration of the placental and blood-brain barriers. In an effort to enhance the potency of DALDA, analogues containing 2',6'-dimethyltyrosine (Dmt), N,2',6'-trimethyltyrosine (Tmt), 2'-methyltyrosine (Mmt) or 2'-hydroxy,6'-methyltyrosine (Hmt) in place of Tyr1, or Orn or alpha,gamma-diaminobutyric acid (A2bu) in place of Lys4, were synthesized. All compounds displayed high mu receptor selectivity in the rat and guinea pig brain membrane binding assays and most of them were more potent mu agonists than DALDA in the mu receptor-representative guinea pig ileum assay, with [Dmt1]DALDA showing the highest potency. Because of its extraordinary mu agonist potency, high mu selectivity, polar character (charge of 3 + ) and metabolic stability, [Dmt1]DALDA has potential for use in obstetrical or peripheral analgesia.
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PMID:Synthesis and in vitro opioid activity profiles of DALDA analogues. 1112 15