How does blood regulate cerebral temperatures during hypothermia?

Macro-modeling of cerebral blood flow can help determine the impact of thermal intervention during instances of head trauma to mitigate tissue damage. This work presents a bioheat model using a 3D fluid-porous domain coupled with intersecting 1D arterial and venous vessel trees. This combined vascular porous (VaPor) model resolves both cerebral blood flow and energy equations, including heat generated by metabolism, using vasculature extracted from MRI data and is extended using a tree generation algorithm.

The identification of a series of novel, soluble non-peptidic neuropeptide Y Y2 receptor antagonists.

The identification and subsequent optimisation of a selective non-peptidic NPY Y2 antagonist series is described. This led to the development of amine 2, a selective, soluble NPY Y2 receptor antagonist with enhanced CNS exposure.

The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure.

The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.

The identification and optimisation of novel and selective diamide neuropeptide Y Y2 receptor antagonists.

A novel small molecule NPY Y2 antagonist (3) identified from high throughput screening is described. A subsequent SAR study and optimisation programme based around this molecule is also described, leading to the identification of potent and soluble pyridyl analogue 36.