Design, synthesis and pharmacological evaluation of novel heterocyclic guanidine derivatives as alpha?-adrenoceptor antagonists for the treatment of depression

THESIS 10156Messages travel through the brain and nervous system in two ways, the first is in the form of an electrical impulse, called an action potential, which travels along a cell called a neuron. The second is via a chemical messenger known as neurotransmitter, which travels through the gap between two neurons. The process by which the neurotransmitter travels through the intracellular gap or synapse is known as neurotransmission (Figure 1.1). Neurotransmitters are taken up into storage vesicles at the end of the presynaptic neuron or axon terminus. There are two pools of storage vesicle in the neuron: the first pool or proximal pool are vesicles which are close to the cell membrane that can fuse with the membrane after an action potential and are thus ready for immediate release. The second pool consists of reserve vesicles which are further away from the membrane, which can be recruited into the proximal pool after the release of neurotransmitters from the proximal pools. When an action potential reaches the presynaptic terminus, it alters the polarity of the cell membrane causing calcium ion channels on the cell membranes to open, which results in an influx of Ca 2+ into the neuron. This in turn causes storage vesicles to fuse with the cell membrane, releasing the neurotransmitter they contain into the synapse. From there they diffuse across the synapse and can bind to receptors on the post synaptic neuron. If the number of binding events which occur exceed a threshold amount, a new action potential is fired in the post synaptic neuron propagating the signal. These postsynaptic receptors can either be ion channels which allow a specific ion or ions to enter the cell on receptor binding and thus affect the electrical potential of the cell directly, or they can be another protein which is altered by the receptor binding and causes a cascade of further binding events to occur. These types of receptor are respectively known as ionotropic and metabotropic receptors