Figure 46 Chemical structures of selected smallmolecule monoamine neurotransmitters

inhibitors achieved a billion dollars or more in sales, among these being citalopram (Celexa, Forest), fluoxetine (Prozac, Lilly), paroxetine (Paxil, GlaxoSmithKline), sertraline (Zoloft, Pfizer), and venlafaxine (Effexor, Wyeth).366

The dopamine transporter (DAT) - a Na+ and CP-dependent neuronal transmembrane protein - was first cloned in the early 1990s, and is involved in locomotor control, including functions lost in Parkinson's disease. DAT is also involved in reward systems, and thus in addiction to drugs such as amphetamine and cocaine, and in ADHD and Tourette's syndrome, among other illnesses.367-371 Indeed, the actions of many small molecule neurotransmitters containing a basic amine are modulated through transporter sites, including those of adrenaline and noradrenaline (epinephrine or norepinephrine), dopamine, histamine, and serotonin (Figure 46). That is, transporters serve to modulate synaptic neurotransmitter levels through reuptake into nerve terminals, and once inside they are taken up into vesicles via different transporters (Figure 47). These effects lend themselves to being studied via in vivo imaging techniques, as outlined later.

Multidrug and drug-specific transporters are involved in the efflux of anticancer and antibiotic chemotherapeutics, which leads to significant resistance in cancer cells and a variety of pathogenic organisms, including bacteria, fungi, and parasites.372 This is often referred to as multidrug resistance (MDR), with P-glycoprotein (P-gp) being a common MDR site in cancer cells. P-gp first generated interest when it was discovered in the late 1980s to be overexpressed in cancer cells. Some drugs, including verapamil (Figure 48), a calcium channel blocker, have been found to inhibit MDRs.373 While such inhibitors might eventually prove useful in dealing with resistance in cancer and infectious diseases, success to date has been limited.

Transporters have also been exploited in drug delivery. The use of Pluronic block copolymers to modulate P-gp-mediated BBB drug efflux has been studied. These polymers have been demonstrated to enhance BBB penetration.374 The choline transporter has also been proposed as a BBB vector for drug delivery.375 Other drug delivery examples are described below.


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