ABSTRACT
Patients with bone cancer report severe pain and receive mu-opioids. We developed a family of peptidomimetic delta-agonists, one of which H2N-Tyr-dVal-Gly-Phe-Ala-OH ([dVal(L)2,Ala(L)5]E) binds with a 1700x affinity at the delta versus mu receptor. To examine the systemic analgesic efficacy of this delta-agonist versus morphine in osteosarcoma pain, osteosarcoma cells are injected into one femur of the anesthetized mouse. After 10-18 days, a decalcification of the injected femur occurs along with a pronounced tactile allodynia. IP morphine and [dVal(L)2,Ala(L)5]E produced a dose-dependent reversal of allodynia with the respective ED50 values being 5.3+/-1.9 mg/kg for morphine and 1.3+/-0.3 mg/kg for [dVal(L)2,Ala(L)5]E. Plotting peak effect versus area under the analgesic curve for doses of morphine and [dVal(L)2,Ala(L)5]E revealed overlapping curves suggesting that for a given effect, [dVal(L)2,Ala(L)5]E produced a similar duration of action as morphine. These effects were reversed by IP naloxone (3 mg/kg). IP naltrindole (1 mg/kg) preferentially reversed [dVal(L)2,Ala(L)5]E. The upper dose effects of morphine but not [dVal(L)2,Ala(L)5]E were limited by pronounced hyperactivity. No other effects were noted. These results show that IP [dVal(L)2,Ala(L)5]E through a delta receptor produces analgesia equal in efficacy to that of morphine but with a 4.5-fold greater potency. Over the doses examined, morphine actions were side effect limited. The delta side effects were not so limited, suggesting a favorable therapeutic ratio for delta-agonists in this pain model. These studies suggest that a systemically delivered delta-opioid agonist has pronounced analgesic properties on a preclinical cancer pain model.
Subject(s)
Analgesics/administration & dosage , Bone Neoplasms/complications , Hyperalgesia/prevention & control , Osteosarcoma/drug therapy , Pain Threshold/drug effects , Receptors, Opioid, delta/agonists , Animals , Arthralgia/etiology , Arthralgia/physiopathology , Arthralgia/prevention & control , Bone Neoplasms/drug therapy , Bone Neoplasms/physiopathology , Dose-Response Relationship, Drug , Hyperalgesia/etiology , Hyperalgesia/physiopathology , Male , Mice , Mice, Inbred C3H , Morphine/administration & dosage , Osteosarcoma/complications , Osteosarcoma/physiopathology , Touch , Treatment OutcomeABSTRACT
[reaction: see text] The tricyclic indeno-tetrahydropyridine core of haouamine A, containing five of the seven rings of the natural product, was constructed by a simple, concise route that features an acid-catalyzed Friedel-Crafts ring closure.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Indenes/chemistry , Pyridines/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Indenes/chemical synthesis , Molecular Structure , Pyridines/chemical synthesisABSTRACT
[Reaction: see text] Enantiocontrolled synthesis of alpha-methyl amino acids proceeds via the regioselective organocuprate opening of Bn2N-alpha-methylserine-beta-lactone. From this chiral intermediate, a wide variety of alpha-methyl amino acids and building blocks were synthesized in excellent yields.
Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Lactones/chemistry , Methane/chemistry , Serine/analogs & derivatives , Molecular Structure , Serine/chemistry , StereoisomerismABSTRACT
A century has passed since Emil Fischer won the Nobel Prize in chemistry. From his first synthesis of glycyl-glycine in 1901 he has been a luminary to peptide chemists over the past 100 years. In this paper, a brief summary of some of the major accomplishments in peptide chemistry will be covered followed by a description of several of our own endeavours in peptide chemistry which arose from the discoveries of the giants of our field. We will include the development of a novel activating agent (DEPBT), the synthesis of a novel building block, alpha-methyl-D-cysteine, its incorporation into biologically active opioids, and conclude with the synthesis of dendritic collagen mimetics.
Subject(s)
Peptides/chemical synthesis , Peptides/history , Collagen/chemistry , History, 20th Century , History, 21st Century , Molecular Mimicry , Molecular Structure , Nobel Prize , Opioid Peptides/chemistry , Organophosphates/chemistry , Peptides/chemistry , Triazines/chemistryABSTRACT
[reaction: see text] We report here the enantioselective synthesis of Boc-alpha-methyl-d-cysteine(PMB)-OH and lanthionine building blocks through the regioselective ring opening of key intermediate Boc-alpha-methyl-d-serine-beta-lactone.
