ABSTRACT
Theoretical and structural studies followed by the directed synthesis and in vitro biological tests lead us to novel noncovalent thrombin pseudopeptide inhibitors. We have incorporated an azapeptide scaffold into the central part of the classical tripeptide D-Phe-Pro-Arg inhibitor structure thus eliminating one stereogenic center from the molecule. A series of compounds has been designed to optimize the occupancy of the S2 pocket of thrombin. Increased hydrophobicity at P2 provides an enhanced fit into this active site S2 pocket. In the present paper, we also report on the structure of these inhibitors in solution and conformational analysis of inhibitors in the active site in order to asses the consequences of the replacement of the central alpha-CH by a nitrogen functionality. In vitro biological testing of the designed inhibitors shows that elimination of R, S stereoisomerism and restriction of conformational freedom influences the binding of inhibitors in a favorable fashion.
Subject(s)
Antithrombins , Aza Compounds/chemical synthesis , Enzyme Inhibitors , Oligopeptides/chemistry , Phenylalanine , Antithrombins/chemical synthesis , Antithrombins/chemistry , Antithrombins/pharmacokinetics , Antithrombins/pharmacology , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Binding Sites , Catalysis , Combinatorial Chemistry Techniques/methods , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Molecular Mimicry , Molecular Structure , Nipecotic Acids/pharmacology , Oligopeptides/pharmacology , Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacokinetics , Phenylalanine/pharmacology , Serine/analogs & derivatives , Serine/pharmacology , Spectrophotometry, Infrared , Spectroscopy, Fourier Transform Infrared , Stereoisomerism , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To report the early experience of a multiagency child psychiatric consultation service. METHOD: The program is described, and the demographic characteristics of clients referred to the consultation program over the first 25 months of operation are presented. Referrals were examined for demographics and the questions consultees wanted to have answered. RESULTS: In 59 of 100 consultations, physical and/or sexual abuse was proved or highly suspected. In 82 of the 100 cases, consultees had questions pertaining to management issues. Questions related to diagnostic issues numbered 62, and there were 45 questions about safety issues. CONCLUSION: Effective psychiatric consultations services to rural areas can be established. Once established, the questions of consultees can provide an effective training ground for future community-oriented child psychiatrists.
