Subject(s)
Brain Injuries, Traumatic/complications , Headache/etiology , Intracranial Thrombosis/diagnostic imaging , Intracranial Thrombosis/etiology , Venous Thrombosis/diagnosis , Venous Thrombosis/etiology , Adult , Brain Injuries, Traumatic/diagnostic imaging , Cerebral Angiography , Computed Tomography Angiography , Headache/diagnostic imaging , Humans , MaleABSTRACT
A new and convenient stereocontrolled synthesis of the optically pure (S)-alpha-methyl,alpha-amino acids 6(a-d) that exploits the chiral synthon 1,4-N,N-[(S)-1-phenylethyl]-piperazine-2,5-dione (1) is described. The (S)-1-phenylethyl group, bonded to each of the N-atoms of the 2,5-diketopiperazine, acts as a chiral inductor in the first alkylation, while the steric hindrance appears to be the determining factor of stereocontrol in third and forth alkylation.
Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Alanine/analogs & derivatives , Alanine/chemical synthesis , Alanine/chemistry , Aminobutyrates/chemical synthesis , Aminobutyrates/chemistry , Crystallography, X-Ray , Diketopiperazines/chemical synthesis , Diketopiperazines/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Stereoisomerism , Valine/chemical synthesis , Valine/chemistryABSTRACT
Twelve derivatives of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) antagonist 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide (Comp 24) were synthesized and tested in binding experiments performed on CHO(hNOP) cell membranes. Among them, a novel interesting NOP receptor antagonist (compound 35) was identified by blending chemical moieties taken from different NOP receptor ligands. In vitro in various assays, Compound 35 consistently behaved as a pure, highly potent (pA(2) in the range 8.0-9.9), competitive and NOP selective antagonist. However compound 35 was found inactive when challenged against N/OFQ in vivo in the mouse tail withdrawal assay. Thus, the usefulness of the novel NOP ligand compound 35 is limited to in vitro investigations.
Subject(s)
Narcotic Antagonists , Piperidines/chemistry , Piperidines/pharmacology , Receptors, Opioid/metabolism , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Animals , Behavior, Animal/drug effects , CHO Cells , Cricetinae , Cricetulus , Electric Stimulation , Guinea Pigs , Humans , Ileum/drug effects , Male , Mice , Piperidines/administration & dosage , Piperidines/chemical synthesis , Protein Binding , Rats , Rats, Sprague-Dawley , Spiro Compounds/administration & dosage , Spiro Compounds/chemical synthesis , Structure-Activity Relationship , Vas Deferens/drug effects , Nociceptin ReceptorABSTRACT
On the basis of a Janssen's patent, we approached a new synthesis of some 1,3,5-triazin-4,6-diones as potential non peptidic prokineticin receptor antagonists, containing the following substitutions: (N(1) and N(5) link a 4-methoxybenzyl and a 4-ethylbenzyl, respectively; C(2) can link an amino-ethyl-guanidine (reference compound 1) or an ethylendiamine (2) or an amino-ethyl-amino-2-imidazoline (3). New compounds were assessed for PKR1 and PKR2 affinity. Antagonist properties were evaluated as inhibition of 1 nM Bv8-induced intracellular Ca2+ mobilization.
Subject(s)
Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Peptide/antagonists & inhibitors , Triazines/pharmacology , Binding Sites/drug effects , Calcium/metabolism , Calcium Signaling/drug effects , Dose-Response Relationship, Drug , Drug Design , Gastrointestinal Hormones/chemistry , Humans , Ligands , Molecular Structure , Neuropeptides/chemistry , Stereoisomerism , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistryABSTRACT
Here we report the synthesis and biological properties of peptide-based molecules bearing constrained analogues of phenylalanine at the C-terminal. Compounds were tested as proteasome subunits' inhibitors. Dehydro-peptides showed good inhibition, in particular against trypsin-like (T-L) proteasome activity while some C-terminal Tic-derivatives inhibit only caspase-like activity in enzymatic beta1 subunits with a certain degree of efficacy. The best analogues of the series demonstrated good resistance to proteolysis and a capacity to permeate the cell membrane.
Subject(s)
Cysteine Proteinase Inhibitors/pharmacology , Phenylalanine/chemistry , Proteasome Inhibitors , Cell Line , Cysteine Proteinase Inhibitors/chemistry , Enzyme Stability , Humans , Magnetic Resonance Spectroscopy , Proteasome Endopeptidase Complex/metabolismABSTRACT
A wide range of activities are induced by Lys when introduced at C-terminus of the delta-opioid Dmt-Tic pharmacophore through the alpha-amine group, including: improved delta-antagonism, mu-agonism and mu-antagonism. Here we report the synthesis of a new series of compounds with the general formula H-Dmt-Tic-NH-(CH(2))(4)-CH(R)-R' (R=-NH(2), -NH-Ac, -NH-Z; R'=CO-NH-Ph, -CO-NH-CH(2)-Ph, -Bid) in which Lys is linked to Dmt-Tic through its side-chain amine group. All new compounds (1-9) displayed potent and selective delta-antagonism (MVD, pA(2)=7.81-8.27), which was independent of the functionalized alpha-amine and carboxylic groups of C-terminal Lys. This behaviour suggests a direct application as a prototype intermediate, such as Boc-Dmt-Tic-epsilon-Lys(Z)-OMe, which could be successfully applied in the synthesis (after Z or methyl ester removal) of unique designed multiple ligands containing the pharmacophore of the quintessential delta-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand.
