Binding monoamines

Tricyclic antodepressants are an important group of antidepressants. They block the uptake of monoamines by nerve terminals by competing for the binding site of the reuptake carrier protein. 

In the monoamine receptors the ligand-binding domain is located within the transmembrane helices. A pocket is formed between TM3, TM5 and TM6 where the agonist binds. A conserved aspartate residue in TM3 (Asp-113 in the /(-adrenoceptor) and a... 

While the agonist binding domain is thought to be within the transmembrane domains for the monoamine and nucleotide receptors, neuropeptides are thought to bind close to the membrane surface on the extracellular domains of the receptor. It is still not clear whether non-peptide antagonists bind at the same or a different site on the receptor. 

As with the other monoamines, 5-HT is found primarily in storage vesicles (30-35 nm diameter) where serotonin-binding proteins (SBPs) have also been identified. These seem to form a macromolecular complex with 5-HT. In fact, three such proteins have now been characterised, but only one of them, 45kDa SBP, appears to be secreted into the synapse along with 5-HT. Whether they serve any role other than forming an osmotically inert storage matrix for 5-HT is unknown. 

Monoamine concentrations or receptor binding in brain tissue post-mortem. 

The affinity (Kj values) observed for [ H]MDA and [ HJMDMA binding were similar to the effective doses (i.e., ED50 or K] values) of MDA and MDMA reported for various pre- and postsynaptic monoamine markers, such as serotonin and dopamine release (Johnson et al. 1986), monoamine transport (Steele et al. 1987), and multiple brain, ligand binding sites (Battaglia et al. 1988). 

The pharmacology of [ HjMDA binding was determined by examining the effects of other monoamine reuptake blockers and related amphetamine... 

Retinal, Monoamines, and Other Small Messengers Bind between the... 

Monoamine Antagonists Often Bind Close to Where the Agonist Binds... 

D-amphetamine stimulates the release of monoamines independently of the electrical activity of the neuron. This release leads to an increased concentration of monoamines in the synaptic cleft and, thus, an increase in receptor stimulation. Drugs, such as amphetamine, that do not bind to receptors, but increase the availability of the neurotransmitter by stimulating its release or inhibiting its inactivation, are called indirect agonists. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Zubieta, J. K., Huguelet, P., Ohl, L. E. etal. High vesicular monoamine transporter binding in asymptomatic bipolar I disorder sex differences and cognitive correlates. Am. J. Psychiatry 157 1619-1628, 2000. 

Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants. By interacting with these transporters (Chs 12 and 13), psychomotor stimulants increase extracellular levels of monoamine neurotransmitters. Cocaine is a monoamine uptake inhibitor. The reinforcing effects of cocaine correlate best with its binding potency at the DAT. However, experiments with monoamine transporter-deficient mice suggest that cocaine actions at... 

Insights From Endogenous and Engineered Zn2+ Binding Sites in Monoamine Transporters... 

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