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Development of METx: a Vasopressin Agonist

Patel, SK; (2017) Development of METx: a Vasopressin Agonist. Doctoral thesis , UCL (University College London).

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Abstract

Vasopressin (AVP) was one of the first peptides to be extracted and produced synthetically in the early 1950s. Since then AVP and its analogues have been increasingly researched as both AVP agonists and antagonists have therapeutic uses. Although much time and effort has been used to design potent selective AVP agonists and antagonists, very few have reached the market. AVP agonist analogues have only been approved for diabetes insipidus and variceal bleeding. Current main stay treatment for diabetes insipidus is desmopressin, a synthetic analogue of AVP. Desmopressin is well tolerated by the majority of patients, however severe adverse affects, such as hyponatraemia and water intoxication require a strict fluid intake, restricting fluid intake. Our aim is to develop METx for the treatment of diabetes insipidus to help overcome some of the limitations in lifestyle. The solubility and aggregation of METx was measured using the shake flask and pyrene assay respectively. The activity of METx was determined by measuring cAMP production by MDCK cells. The activity of METx was compared to that AVP, the natural agonist of the vasopressin receptor. Formulation studies were performed using GCPQ to create a formulation that could be used subcutaneously or orally. The stability of GCPQ formulations was determined in plasma, simulated gastric fluid (SGF) and rat intestinal wash (RIW). The activity of METx was measured in vivo by monitoring the urine production of rats upon administration of METx intravenously. METx was practically insoluble in aqueous solvents such as water and PBS, with increased solubility in organic solvents. Using TEM imaging aggregation of METx of was seen, the pyrene assay determined the critical micelle concentration to be 27.4mg l-1. METx was found to be a partial agonist of the vasopressin 2 receptor naturally expressed on the MDCK cells, it exhibited a similar EC50 to AVP. Formulating with GCPQ a ratio of 1:5 (METx:GCPQ) was found to be the most stable in plasma, SGF and RIW. In vivo studies found METx to have a dose dependent reduction in urine production in rats, with 40mg kg-1 rats not producing any urine. The experiments suggest the development of a novel partial agonist of the vasopressin 2 receptor in vitro. The addition of GCPQ results in the formation of nanoparticles, with a ratio of 1:5 (METx:GCPQ) most stable in plasma, SGF and RIW. In vivo experiments resulted in reduced urine production by rats, in a dose responsive manner.

Type: Thesis (Doctoral)
Title: Development of METx: a Vasopressin Agonist
Event: UCL (University College London)
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/1554680
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