ABSTRACT
A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Receptors, Cholecystokinin/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Callithrix , Cerebral Cortex/metabolism , Crystallography, X-Ray , Guinea Pigs , HeLa Cells , Humans , In Vitro Techniques , Membranes , Mice , Models, Molecular , Pancreas/metabolism , Radioligand Assay , Rats , Receptor, Cholecystokinin A , Receptor, Cholecystokinin B , Receptors, Cholecystokinin/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of 3-ureido and 3-carbamate derivatives of 1,5-benzodiazepines bearing bridged cycloalkyl substituents at N-1 are reported. Their activity as CCK-B receptor ligands is briefly discussed.
Subject(s)
Benzodiazepines/chemical synthesis , Receptors, Cholecystokinin/antagonists & inhibitors , Animals , Benzodiazepines/pharmacology , Guinea Pigs , In Vitro Techniques , Ligands , Receptor, Cholecystokinin BSubject(s)
Benzodiazepines/chemical synthesis , Benzodiazepines/metabolism , Hydrocarbons, Halogenated/chemical synthesis , Hydrocarbons, Halogenated/metabolism , Receptors, Cholecystokinin/metabolism , Animals , Benzodiazepines/pharmacology , Guinea Pigs , Hydrocarbons, Halogenated/pharmacology , Kinetics , Ligands , Receptor, Cholecystokinin B , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We have synthesized, by solution methods, and fully characterized a variety of (alpha Me)Phe derivatives and model peptides (to the pentapeptide level). The results of the solution conformational analysis, performed by using infrared absorption and 1H nuclear magnetic resonance, support the view that the (alpha Me)Phe residue is a stronger beta-turn and helix promoter than the unmethylated Phe analog. A comparison is also made with the conclusions extracted from published work on peptides rich in other C alpha-alkylglycyl residues.
Subject(s)
Oligopeptides/chemistry , Phenylalanine/analogs & derivatives , Amino Acid Sequence , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Sequence Data , Phenylalanine/chemistry , Solutions/chemistry , Spectrophotometry, InfraredABSTRACT
Conformational energy computations on Ac-L-(alpha Me)Val-NHMe indicate that turns and right-handed helical structures are particularly stable conformations for this chiral C alpha-methyl, C alpha-alkylglycyl residue. We have synthesized and characterized a variety of L-(alpha Me)Val derivatives and peptides (to the pentamer level). The results of the solution conformational analysis, performed using infrared absorption, 1H nuclear magnetic resonance, and circular dichroism, are in general agreement with those obtained from the theoretical investigation, in the sense that the L-(alpha Me)Val residue turns out to be a strong beta-turn and right-handed helix former. A comparison is also made with the conclusions extracted from published work on peptides rich in other C alpha-methyl, C alpha-alkylglycyl residues.
Subject(s)
Glycine/analogs & derivatives , Peptides/chemistry , Protein Conformation , Stereoisomerism , Circular Dichroism , Magnetic Resonance Spectroscopy , Spectrophotometry, InfraredABSTRACT
The molecular and crystal structures of one derivative and three model peptides (to the pentapeptide level) of the chiral C alpha,alpha-disubstituted glycine C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] have been determined by X-ray diffraction. The derivative is mClAc-L-(alpha Me)Val-OH, and the peptides are Z-L-(alpha Me)Val-(L-Ala)2-OMe monohydrate, Z-Aib-L-(alpha Me)Val-(Aib)2-OtBu, and Ac-(Aib)2-L-(alpha Me)Val-(Aib)2OtBu acetonitrile solvate. The tripeptide adopts a type-I beta-turn conformation stabilized by a 1----4N--H...O = C intramolecular H-bond. The tetra- and pentapeptides are folded in regular right-handed 3(10)-helices. All four L-(alpha Me)Val residues prefer phi, psi angles in the right-handed helical region of the conformational map. The results indicate that: (i) the (alpha Me)Val residue is a strong type-I/III beta-turn and helix former, and (ii) the relationship between (alpha Me)Val chirality and helix screw sense is the same as that of C alpha-monosubstituted protein amino-acids. The implications for the use of the (alpha Me)Val residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed.
Subject(s)
Glycine/analogs & derivatives , Peptides/chemistry , Amino Acid Sequence , Chemical Phenomena , Chemistry, Physical , Crystallization , Glycine/chemistry , Molecular Sequence Data , Molecular Structure , Protein Conformation , X-Ray DiffractionABSTRACT
CHO-L-Met-L-Leu-L-(alpha Me)Phe-OMe, an analog of the formyl methionyl tripeptide chemoattractant CHO-L-Met-L-Leu-L-Phe-OH, was synthesized by solution methods and fully characterized. This compound was prepared to determine the effect of the incorporation of a conformationally restricted C alpha,alpha-disubstituted alpha-amino acid residue at position 3 on the relation of three-dimensional structure to biological activity. The peptide was tested for its ability to induce granule enzyme secretion from rabbit peritoneal polymorphonuclear leukocytes. In parallel, a conformational analysis was performed in the crystal state by x-ray diffraction and in organic solution by infrared absorption and 1H nuclear magnetic resonance. These biological and conformational data are discussed in relation to those of the prototype tripeptide and its methyl ester.
Subject(s)
Chemotactic Factors/chemistry , N-Formylmethionine Leucyl-Phenylalanine/analogs & derivatives , Amino Acid Sequence , Animals , Biological Assay , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Sequence Data , N-Formylmethionine Leucyl-Phenylalanine/chemistry , Protein Conformation , Rabbits , Spectrophotometry, Infrared , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
The conformationally restricted CHO-L-Met-Xxx-L-Phe-OY (where Xxx = Aib, Ac3c, Ac5c, Ac6c, and Ac7c; Y = H, Me) tripeptides, analogs of the chemoattractant CHO-L-Met-L-Leu-L-Phe-OH, have been synthesized in solution by classical methods and fully characterized. Compounds were compared to determine the combined effect of backbone conformational preferences and side-chain bulkiness on the relation of three-dimensional structure to biological activity. Each peptide was tested for its ability to induce granule enzyme secretion from rabbit peritoneal polymorphonuclear leukocytes. In parallel, a conformational analysis on the CHO-blocked peptide and their tertbutyloxycarbonylated synthetic precursors was performed in the crystal state and in solution using X-ray diffraction, infrared absorption, and 1H nuclear magnetic resonance. The biological and conformational data are discussed in relation to the proposed model of the chemotactic peptide receptor of rabbit neutrophils.
