Academic literature on the topic 'PhD thesis pharmacology'

Peptides play key structural and functional roles in biochemistry, pharmacology, and neurobiology, and are important probes for research in enzymology, immunology, and molecular biology. The amino acid building blocks can be among the 20 genetically encoded L-residues, or else unusual ones, and the sequences can be linear, cyclic, or branched. It follows that rapid, efficient, and reliable methodology for the chemical synthesis of these molecules is of utmost interest. A number of synthetic peptides are significant commercial or pharmaceutical products, ranging from the sweet dipeptide L-Asp-L-Phe-OMe (aspartame) to clinically used hormones such as oxytocin, adrenocorticotropic hormone, calcitonin, and gonadotropin releasing hormone (GnRH) super-agonists. Synthesis can lead to potent and selective new drugs by judicious substitutions that change functional groups and/or conformations of the parent peptide. These include introduction of N- or C-alkyl substituents, unnatural or D-amino acids, side-chain modifications including sulfate or phosphate groups or carbohydrate moieties, and constraints such as disulfide bridges between half-cystines or side-chain lactams between Lys and Asp or Glu. Commercially important products that evolved from such studies include protease inhibitors, such as captopril and other angiotensin converting enzyme (ACE) inhibitors, peptidomimetic HIV protease inhibitors, and the somatostatin analog lanreotide. Most of the biologically or medicinally important peptides which are the targets for useful structure-function studies by chemical synthesis comprise under 50 amino acid residues, but occasionally a synthetic approach can lead to important conclusions about small proteins (full or domains) in the 100-200 residue size range. Methods for synthesizing peptides are divided conveniently into two categories: solution (classical) and solid-phase pep tide synthesis (SPPS). The classical methods have evolved since the beginning of the twentieth century, and they are described amply in several reviews and books (Wünsch, 1974; Finn and Hofmann, 1976; Bodanszky and Bodanszky, 1984; Goodman et al, 2001). The solid-phase alternative was conceived and elaborated by R. B. Merrifield beginning in 1959, and has also been covered comprehensively (Erickson and Merrifield, 1976; Birr, 1978; Barany and Merrifield, 1979; Stewart and Young, 1984; Merrifield, 1986; Barany et al., 1987, 1988; Kent, 1988; Atherton and Sheppard, 1989; Fields and Noble, 1990; Barany and Albericio, 1991; Fields et al., 1992; Gutte, 1995; Fields, 1997; Lloyd-Williams et al., 1997; Chan and White, 2000; Kates and Albericio, 2000).

Forskolin stimulates adenylate cyclase by interacting with the catalytic subunit and inhibits platelet aggregation. This inhibition is greatly potentiated by adenosine (Ado) which stimulates adenylate cyclase through membrane-bound Ado receptors. Forskolin is 2-4 fold more potent as an inhibitor of collagen-induced rat platelet aggregation as compared to human platelets (IC50 values, in rat PRP, 0.5-0.8 μM; in human PRP, 1.5-2 μM). However, if the blood is pretreated with adenosine deaminase (ADA), an enzyme that degrades Ado to inosine, the inhibitory action of forskolin is greatly reduced pr