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Title: NMR studies of tachykinin analogues
Author: Upton, Richard J.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1990
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The tachykinins are highly active mediators of neuronal action in the CNS. In order to understand their action and provide templates for drug development, analogues based on the active sequence of Substance P have recently been synthesised. These analogues often have conformational constraints incorporated into their sequence. For instance, the linear agonists [L and D-Pro9]SP6-11 (l) & (2) and [SucAsp6, NMePhe8]SP6-11 (3) have receptor subtype selectivities for NK1, NK2 and NK3 respectively. The novel cyclic peptides [GlnTrpPheGlyLeuMet] (4) and [GlnTrpPheGly[ANC-2]MetLeu] (5), and their linear counterpart AcLeuMetGlnTrpPheGlyNH2 (6) have high antagonist activity for the NK2 receptor. The NK2 receptor is the preferred subtype for endogenous agonist neurokinin A (7). Knowing their conformational properties and rationalising these against their activities, may provide the basis for understanding the process of molecular recognition and lead to directed drug design. The conformational properties of these peptides in DMSO and methanol were investigated using 1 and 2D NMR techniques. Particularly important was the application of the recently developed ROESY and TOCSY experiments, which greatly simplify the assignment and conformational analysis of these compounds. Distinct conformations were found for the linear analogues (1), (2) and (3). This was shown to be due to cis/trans isomerism about the N-alkylated peptide bond. However, despite the known turn preferences for the constraints incorporated into these peptides, no global conformational characteristics were identified. All the linear peptides were found to exist in a chiefly extended state in DMSO. Peptides (1) and (2) occupied 'random coil' conformational space in methanol. The cyclic peptides (4) and (5) exhibited specific conformational preferences. Using restraints provided by their NMR parameters, molecular modelling showed a ss II turn in the LeuMet region for both of these peptides. The similarity in conformation of these cyclics may explain their analogous pharmacology. The synthesis of novel Substance P analogues with a beta-lactam constraint in the (RS)Phe[ANC-2]Gly position is presented, together with the attempted cyclisation of the resulting linear peptides.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available