Medical brain Notes 3

  Pharmacology of catecholamines and of serotonin   The catecholamines (named for the catechol moiety that is part of their structure, Figure 10.1) are important in both the peripheral autonomic system and the central nervous system. Key functions in the periphery are regulation of heart rate and blood pressure. In the brain, they are in-volved in the regulation of posture and movement, and of psychical functions such as mood and alertness. Although all three mediators occur both peripherally and centrally, dopamine and norepinephrine are the main ones found as transmitters in the brain, whereas norepinephrine and epinephrine are more important than dopamine in the periphery. Norepinephrine occurs in both synapses and in the adrenal gland, whereas epinephrine is mainly found in the adrenal gland and thus really is a hormone more than a transmitter.   Serotonin is a mediator similar to the catecholamines that is derived from tryptophan rather than tyrosine (Figure 10.2b). ...

  Biosynthesis and degradation of catecholamines The catecholamines - dopamine, norepinephrine, and epinephrine are successively derived from tyrosine. Syn-thesis occurs in the nerve terminals and in the adrenal gland. Tyrosine hydroxylase catalyzes the first step (Figure 10.2a) and is the major site of regulation (inhibition by dopamine and noradrenaline, activation by cAMP). This step gives rise to 3,4-dihydroxyphenylalanine (L-DOPA), which in turn is a substrate for L-aromatic acid decarboxylase. Decarboxylation yields the first mediator, dopamine. The sub-strate specificity of the decarboxylase is rather low, and it thus will also accept 5-hydroxytryptophan (the precursor of serotonin, Figure 10.2a) and a variety of synthetic analogs, as we shall see later. Further hydroxylation of dopamine leads to norepinephrine, and methylation to epinephrine.   The biosynthesis of serotonin is similar to that of dopamine and also involves enzymatic hydroxylation and subsequent decarbox...

  Pharmacokinetic aspects All three catecholamines are rather polar, due to both the hydroxyl groups and the amino group, which will be mostly protonated at physiological pH. They will thus not cross the blood brain barrier easily, so that in effect the cate-cholamine pools in the brain and in the periphery will not interfere with each other. Exclusion by the blood brain bar-rier also applies to many synthetic agonists and antagonists that act on catecholamine receptors, as these compounds often are structurally similar to the physiological media-tors. These drugs are useful to influence the peripheral.

  Drug targets in catecholaminergic synapses In an catecholaminergic synapse, we find several sites that can be targets of drug action (Figure 10.4): 1.    The most straightforward one is, of course, the postsy-naptic receptor, to which both agonists and antagonists will bind. As we have seen before, these receptors oc-cur in various types and subtypes. With the three physiological catecholamines, there is a fairly clear distinc-tion between the  α - and  β -receptors on one hand, which respond to epinephrine and norepinephrine but not dopamine, and the dopaminergic receptors. The major functional difference between epinephrine and nore-pinephrine consists in their activity on the  β 2  receptor subtype, which is very sensitive to the former but not the latter. Synthetic agonists and antagonists (which may or may not closely resemble the natural catecholamines in structure) often have superior type and subtype selectiv-ity, which is both theoretically ...

  Adrenergic receptor agonists and antagonists   The first adrenergic receptor types to be distinguished from each other were the adrenergic  α - and  β -receptors. Initially based on the different cardiovascular effects of epinephrine and norepinephrine, this distinction was borne out more clearly with the synthetic  β -selective agent isoproterenol. Furthermore, subtypes of both  α - and  β -receptors can be distinguished by selective agonists (Figure 10.5). 1. Physiological effects of  α - and  β -selective adrenergic agonists The different cardiovascular effects of  α - and  β -receptors are illustrated in the experiment in Figure 10.6. Phenyle-phrine, an  α -selective agent, causes vasoconstriction and accordingly a rise in blood pressure. The heart has few  α -receptors, so phenylephrine does not accelerate the heart   rate. Rather, the heart rate drops a little, due to an auto-nomic physiological reflex trigger...

  Inhibitors of presynaptic transmitter reuptake Presynaptic reuptake of catecholamines works by cotrans-port of sodium and chloride ions. While the reuptake trans-porters are homologous among the various types of cate-cholaminergic and serotoninergic synapses, the stoichiom-etry of transmitter molecules and co-transported ions ap-pears to vary, as depicted in Figure 10.11a. The transport process is facilitated both by ion concentration gradients and by the resting membrane potential (note that reuptake will cause a net transport of positive charge to the cytosol). Inhibition of presynaptic transmitter reuptake is another very important principle of drug action at adrenergic and serotoninergic synapses. It will have several consequences (Figure 10.11b):   1.    It will increase the concentration of transmitter in the synaptic cleft and, therefore, the postsynaptic stimulato-ry action. 2.    The postsynaptic cells will respond with a reduction of receptors e...

  Inhibition of vesicular storage Vesicular accumulation of catecholamines and of serotonin is inhibited by reserpine (Figure 10.14a). While reserpine initially was believed to inhibit the H + -ATP'ase that gener-ates and maintains a high proton concentration inside the vesicles 6 , it is now clear that reserpine instead binds to the vesicular transmitter transporter that makes use of this pro-ton gradient to move the transmitter uphill its own gradi-ent into the vesicle (Figure 10.14b). The number of protons released for the import of each transmitter molecule is not known with certainty but is likely greater than 1. Reserpine affects both the central nervous system 7  and the peripheral autonomic system. The immediate effect will be the accumulation of transmitter in the cytosol. From there, it may `spill over', possibly by retrograde operation of the specific reuptake transporters, into the synaptic cleft. Accordingly, a transient `sympathomimetic' effect may be seen aft...

  Indirect sympathomimetics A more complex (and still somewhat contentious) mecha-nism of action is found with a group of drugs known as `in-direct sympathomimetics'. Example structures are shown in Figure 10.15a. As you can see, all these structures lack the phenolic –OH groups present in epinephrine. This pre-vents their modification by catechol-O-methyltransferase and slows down their deamination by monoamine ox-idase. It also facilitates their crossing of the blood brain barrier, and it is mostly for their central effects – enhanced vigilance, elation, and suppression of appetite, result-ing in weight loss – that these drugs have been used and abused. Amphetamine and methamphetamine preferen tially act on catecholaminergic synapses, in particular on those containing norepinephrine. In contrast, the substance 3,4-methylenedioxyamphetamine (a.k.a. `ecstasy'; Figure 10.15b) has a stronger effect on serotoninergic synapses. It is likewise popular as a drug of abuse.   Amphetam...

  L-DOPA and carbidopa in the therapy of Parkinson's disease Like the transporters for the catecholamines and serotonin, those for their precursor amino acids are not of very high specificity. This has been exploited in various ways for pharmacotherapy. A very important example is the use of L-DOPA as a pre-drug to substitute dopamine to the brain in patients with Parkinson's disease (Figure 10.18a). Dopamine itself cannot cross the blood brain barrier 13 . However, L-DOPA is accepted by an amino acid carrier that normally transports aromatic amino acids. It can thus enter the brain and there be decarboxylated to dopamine.   Concurrently with its permeation into the brain, howev-er, DOPA will also be decarboxylated in the periphery to dopamine; thus, the overall fraction of DOPA that winds up in the brain is only about 2%. This means that very high dosages will be required for the desired clinical effect, and the periphery would be uselessly troubled with high amounts of dopam...

  'False transmitters' Another drug closely similar to DOPA but used for differ-ent applications is  α -methyl-DOPA (Figure 10.19a). This molecule acts in the peripheral autonomous system but also enters the brain, by the same route as DOPA. It is converted by DOPA decarboxylase to the `false transmitter' α -methyl-dopamine. Like dopamine or norepinephrine,  α -methyl-dopamine is accumulated inside the transmitter vesicles, and released in response to action potentials. While it has no strong effect on postsynaptic  α 1 -receptors, it does ac-tivate  α 2 -receptors. It will therefore inhibit the further re-lease of transmitter without stimulating the postsynaptic neuron. The effect of methyl-DOPA is augmented by the fact that it is fairly resistant to monoamine oxidase. Its mode of action resembles that of clonidine (which accom-plishes the same in a less roundabout manner).   Another example of a `false transmitter' is the drug guanethidine (Figure 10.19b)...