Controlled dopamine (D1) receptor stimulation using photo-responsive substrates

Rajput, Sunil (2019) Controlled dopamine (D1) receptor stimulation using photo-responsive substrates. PhD thesis, University of Nottingham.

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Abstract

Dopamine (2-(3,4-dihydroxyphenyl)ethylamine) is a key neurotransmitter involved in the formation of memory, and the process of learning. This is through the modulation of synaptic plasticity by the activation of cell surface receptors. The exact mechanism by which information from an external environment is processed and stored within our brain is still beyond our scientific knowledge. To determine how these processes work, we must first understand how a network of neurons communicates within a culture. In a model that enables development of our understanding of neuronal communication, continuous monitoring and stimulation of single cells using non-invasive methods is essential. For the development of this model, it is reasonable to treat monitoring and stimulation of cells as separate challenges. This thesis focuses on developing means that enable targeted stimulation of cells.

This project reports the design, synthesis and pharmacological data for novel photo-responsive conjugated dopamine analogues, tethered to surfaces, to control activity at the dopamine D1 receptor. To achieve this, modifications to dopamine were made to identify functional groups, contributing to key binding sites found at the D1 receptor. Synthesis of a photo-responsive spiropyran molecule and conjugation to dopamine using amide formation was used to control the availability of the pharmacophore to the D1 receptor in solution, as well as on to glass substrates and nanoparticles. A reporter gene assay (CRE‑SPAP) was used to determine the potency of the synthesised compounds.

It was shown that modification of the catechol and amino moieties of dopamine affect the potency of the compound at the D1 receptor. Modification of the catechol resulted in no activity, whilst carbamate protection and N-alkyl modifications (aliphatic/aliphatic ether chains) at concentrations above 10-6 M resulted in generation of SPAP. Activation of the receptor was demonstrated using dopamine functionalised nanoparticles, successfully confirming that ligands can be immobilised on solid substrates and maintain their ability to activate surface receptors.

Controlled activation using the spiropyran dopamine analogue was also achieved at the D1 receptor using both the soluble and surface bound compound. It was shown that activity was completely supressed in the closed spiropyran state, whilst the open merocyanine isomer produced activity in the soluble form. When adhered on to a nanoparticle, the closed isomer showed a 17-fold reduction in effective concentration (50%) compared to the open isomer.

This work shows that control of the availability and potency of a neurotransmitter attached to a solid support system to activate a receptor on a cell surface is in principle possible. This paves the way for the design and synthesis of materials which act as photo-pharmaceuticals and enable high spatiotemporal control of the activation of dopamine D1 receptors.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Zelzer, Mischa
Mistry, Shailesh
Russell, Noah
Keywords: Dopamine, D1, Photo-Pharmaceuticals, Smart Responsive Materials, Spiropyran
Subjects: Q Science > QP Physiology > QP351 Neurophysiology and neuropsychology
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 56103
Depositing User: Rajput, Sunil
Date Deposited: 16 Aug 2019 14:47
Last Modified: 06 May 2020 13:17
URI: http://eprints.nottingham.ac.uk/id/eprint/56103

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