A small change in an antidepressant can dramatically change its target in the brain. Understanding this, say Kristian Strømgaard and colleagues at the University of Copenhagen, Denmark, is the key to developing more effective drugs¹

Neurotransmitters are continually at work in our bodies, controlling when we wake up and when we feel hungry and even affecting our emotional state. Given their importance in regulating so many human brain functions it is hardly surprising that dysfunctions in neurotransmitter systems have been implicated in mental and behavioural disorders, from depression to anorexia and drug addiction. 

Neurotransmitters transmit signals from neuron (nerve cell) to neuron via junctions called synapses and work by interacting with receptor proteins in the cell membranes. Levels of the monoamine neurotransmitters serotonin (5-hydroxytryptamine), norepinephrine (or noradrenaline) and dopamine are tightly regulated outside the cells by three unique, but closely related transporter proteins: SERT (serotonin), NET (norepinephrine) and DAT (dopamine). These proteins are found in the membranes of the presynaptic neurons - the cells that send the signals - where they are responsible for moving the neurotransmitters into the neurons from the extracellular space.

5-Hydroxytryptamine and norepinephrine are the natural substrates for transporter proteins SERT and NET

The transporters' importance in treating mental disorders is highlighted by the many drugs currently used to target SERT, NET and DAT, including those used to treat anxiety and attention-deficit hyperactivity disorder. Moreover, drugs of abuse, such as cocaine and amphetamines such as 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy), also bind to these transporters.  SERT and NET blockers, which increase extracellular serotonin and norepinephrine levels, have found unparalleled use in treating clinical depression and related disorders. 

Tricyclic antidepressants (TCAs) formed the first generation of monoamine transporter inhibitors developed as antidepressants and represented a major therapeutic breakthrough in the 1950s. However, their broad activity across a variety of receptors results in some severe side-effects. As TCAs' clinical effect began to be attributed to their activity at monoamine transporters, the 1960s and 1970s saw medicinal chemists focus their efforts on developing a new generation of inhibitors with selectivity for these proteins. This resulted in the selective serotonin reuptake inhibitors (SSRIs), which are the most prescribed class of antidepressants today. One of the first developed and best known of these is fluoxetine (Prozac), which was approved for use by the US Food and Drug Administration in 1987.

Considering that monoamine transporter drugs have now been used for over four decades, it is surprising how little is known about how they work at the molecular level and how the various drug types can bind and block transporters selectively. Several structure-activity relationship studies of SSRIs have shown that even very subtle modifications of these compounds can change their pharmacological profile. Fluoxetine, which has SERT selectivity, is a prominent example: replacing its para-trifluoromethyl group with an ortho-methoxy group leads to a compound that is very selective for NET. One would expect such similar molecules to bind in a similar way in the SERT and NET binding pockets, suggesting that their subtle structural differences reflect corresponding differences in the binding pockets. 

A major obstacle to understanding how monoamine transporter drugs work has been a complete lack of structural details of the antidepressant binding sites in the transporters. However, breakthroughs have been made. Specific amino acids in SERT and NET have been identified as important for antidepressant recognition. Another turning point was the resolution of the x-ray crystal structure of a bacterial homologue of the human transporters, a leucine transporter (LeuT) from the thermophile Aquifex aeolicus.² LeuT's structure provides a starting point for constructing 3D models of the inhibitor binding sites in monoamine transporters. It can also be used to help understand existing structure-activity data for antidepressants. 

The information generated from these studies should help us towards understanding how these important drugs bind to their target. In turn, this should allow a much more rational approach to the development of future inhibitors of monoamine transporters, and so might lead to new and more effective drugs. 

Read more in the feature article 'Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters' in issue 25, 2009 of Chemical Communications.

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