Adrenaline Group

FIGURE 27 5 Tyrosine is the biosynthetic precursor to a number of neurotransmit ters Each transformation IS enzyme catalyzed Hydroxy lation of the aromatic ring of tyrosine converts it to 3 4 dihyd roxyphenylalanine (l dopa) decarboxylation of which gives dopamine Hy droxylation of the benzylic carbon of dopamine con verts It to norepinephrine (noradrenaline) and methy lation of the ammo group of norepinephrine yields epi nephrine (adrenaline)... 

Figure 11.16) in which S-adenosy1 methionine transferred a methyl group to norepinephrine to give adrenaline. 

The biological actions of adrenaline and noradrenaline are mediated via nine different G-protein-coupled receptors, which are located in the plasma membrane of neuronal and nonneuronal target cells. These recqrtors are divided into two different groups, a-adrenergic receptors and P-adrenergic recqrtors (see P-adrenergic system). 

Sympatholytic drugs are a group of drugs, which decrease the activity of the sympathetic nervous system, mainly by blocking the action of adrenaline and noradrenaline at adrenoceptors. 

The enzyme /i-phenylethanolamine-A-methyl transferase, which is required to convert noradrenaline (NA) to adrenaline (Ad), is present in the CNS and there is histofluoro-metric evidence (positive staining with antibodies to that enzyme and to tyrosine hydroxylase and dopamine /i-hydroxylase as well) for adrenergic cell bodies in two groups (nuclei) alongside NA neurons of the locus coeruleus (EC) but ventral and lateral (Ci) and dorsal and medial (C2) to it. Projections go to the hypothalamus and in... 

Amine Molecules containing the atom nitrogen (N) and classified according to the nature of their functional group into monoamines (—NH2, e.g., dopamine) secondary amines (—NHR, e.g., adrenaline) tertiary amines (—NR2, e.g., imipramine) and quaternary amines (—N+R3, e.g., acetylcholine) (where R is a methyl group). 

Analogues Chemicals with similar molecular structures (e.g., adrenaline differs from noradrenaline by the addition of one methyl group to the N atom). 

During sleep there is excess production of a substance or group of substances which we will call Y—possibly adrenalin—and which irritates the sensory nerves, waking the sleeper eventually unless he is waked sooner by some other cause—hunger, thirst, digestive disturbances, light on the face, or an alarm clock, for instance. 

Reminiscent of the trend with laboratory studies, most (33 out of 43 cited above) uncontrolled clinical trials with either healthy volunteers or cardiovascular patients suggest that oral and intravenous NO donors at therapeutic doses acutely inhibit platelet activation in vivo (vide supra). Aside from their lack of long-term dosing and a placebo control group, several considerations restrict the predictive clinical value of these uncontrolled clinical studies limited numbers of subjects nonuniform criteria for subject entry and treatment outside of the trial induction of adrenaline or... 

We will conclude this chapter by referring to a term often used for those symptomatic drugs inhibiting the action of the autonomic nervous system by interfering with the effect of the chemical mediators involved. There are two groups. (1) Para-sympatholytic drugs block the action of acetylcholine. These are included within the wider class of spasmolytics which, as the name suggests, check or eliminate spasms. (2) Sympatholytics inhibit the action of adrenaline, noradrenaline and the sympathetic nervous system. 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

A large and diverse group of proteins, including enzymes, cytoskeleton, contractile proteins, and receptors, have been shown to be modified by calpains. Thus, a number of enzymes such as tyrosine hydrolase, tryptophan hydrolase, transglutaminase, protein kinase C, and membrane Ca2+-ATPase are activated by calpain proteolysis [38]. Several receptor proteins, in particular receptors for steroid hormones, growth factors, and adrenaline, are modulated by calpains, which participate also in platelet activation, cell fusion, and mitosis [39], Although the physiological roles of calpains continue to be un-... 

This group of enzymes catalyzes the oxidation of amines. Amine oxidase [EC 1.4.3.4], a flavin-containing enzyme (also known as monoamine oxidase, tyramine oxidase, tyraminase, or adrenalin oxidase) catalyzes the reaction of an organic amine R—CH2—NH2) with dioxygen... 

In terms of chemical structure, amphetamines are very close to epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine, differing in the absence of a hydroxyl group in the aromatic ring and in the aliphatic chain. 

This group consists of j3-adrenergic receptor blockers, the antiarrhythmic activity of which is associated with inhibition of adrenergic innervation action of the circulatory adrenaline on the heart. Because all 8-adrenoblockers reduce stimulatory sympathetic nerve impulses of catecholamines on the heart, reduce transmembrane sodium ion transport, and reduce the speed of conduction of excitation, sinoatrial node and contractibility of the myocardium is reduced, and automatism of sinus nodes is suppressed and atrial and ventricular tachyarrhythmia is inhibited. 

These alkaloids have a phenyl or phenylpropyl nucleus. The group includes simple phenyl amine (tyramine, hordenine), catecholamine (dopamine, noradrenaline, adrenaline), simple tetrahydroisoquinoline (mescaline, anhalamine, anhalonine, anhalonidine), benzylisoquinoline (e.g., papaverine), phthalideiso-quinoline (e.g., noscapine), phenethylisoquinoline (autumnaline, floramultine and kreysigine), tetrahydroisoquinoline (emehne and cephaeline) and terpenoid tetrahydroisoquinoline (secologanin and ipecoside) alkaloids. 

The hydroxyl groups of the phenyl ring are a prerequisite for the activation of all adrenoceptors, if both are absent the molecule has only an indirect sympathomimetic effect (see Fig. 5). Indirect sympathomimetics only have a -, a2 and -adrenoceptor activity since they act via an increase of the noradrenaline concentration in the synaptic cleft. If the methyl-group at the N-position of adrenaline is substituted by a longer or more bulky moiety the molecule gains affinity for the and loses affinity for O -adrenoceptors. An isopropyl moiety is already the optimum for the affinity towards 0-adrenoceptors (isoprenaline), larger substituents enhance only the binding to the 2-subtype (for example fenoterol). 

While the inhibition of noradrenaline re-uptake exerts predominantly an a-adrenergic effect, a selective jS-adrenergic effect can not be obtained by such an indirect mechanism. All selective /3-sympathomi-metics activate the receptors, P -, P2- or both sub-types, directly. The first pure jS-sympathomimetic in clinical use was isoproterenol which is structurally identical to adrenaline except the methyl-moiety at the N-position in the side-chain is replaced by an isopropyl-group. All effects produced by isoproterenol are due to either P -or 62-adrenoceptor stimulation tachycardia, increased stroke volume, decreased vascular resistance, broncho dilatation and, in pregnancy, uterus relaxation. The metabolic effects of isoproterenol are less pronounced than those of adrenaline. 

Optical isomerism of drug molecules is widespread. Many drug molecules only contain one or two chiral centres. A simple example is the naturally occurring neurotransmitter adrenaline. When a compound has no symmetry about a particular carbon atom the carbon atom is said to be a chiral centre. When a compound contains one or more chiral centres it is able to rotate plane-polarised light to the right (+) or the left (-). A chiral centre arises when a carbon atom has four structurally different groups attached to it. 

Using these rules we can assign the absolute configurations for adrenaline structures A and B. Placing the group of lowest priority behind the paper, in this case H. 

Adrenaline is present as a vasoconstrictor in some local anaesthetic injections in a much smaller amount than the local anaesthetic itself, which obscures the absorption of adrenaline in the UV region. The selectivity of UV/visible spectroscopy for the analysis of adrenaline can be increased by complex formation, which occurs between iron (II) and molecules containing a catechol group (Fig. 4.13). These complexes are purple in colour and absorb at ca 540 nm at much longer wavelengths than for instance local anaesthetics, which do not form such complexes. The adrenaline in the injection is quantified against a standard solution of adrenaline. 

Injections of local anaesthetics often contain low concentrations of adrenaline in order to localise the anaesthetic for a time by constricting blood vessels in the vicinity of the injection. Adrenaline can be analysed by straight-phase chromatography, for instance on silica gel, but this generally requires strongly basic conditions under which the catechol group in adrenaline is unstable. Adrenaline is... 

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