Adrenaline receptor interaction

The only exception to this are the nerves which go directly to the adrenal medulla. The neurotransmitter released here is noradrenaline and this stimulates the adrenal medulla to release the hormone adrenaline. This hormone then circulates in the blood system and interacts with noradrenaline receptors as well as other adrenaline receptors not directly fed with nerves. 

There are two types of cell membrane receptor (a and jS) for adrenaline. -Receptors which are inhibited by -blockers such as propanolol are the main type of receptor in muscle, heart, adipose tissue and many other tissues. They interact with and activate adenylate cyclase in the cell membrane so that the effect of adrenaline on muscle or adipose tissue is to increase the concentration of cAMP in the cell and thus to activate protein kinase. Stimulation of glycogen breakdown by adrenaline in muscle is then mediated by a cascade mechanism similar to that involved in the stimulation of glycogenolysis in liver by glucagon (page 353). Breakdown of triglycerides in adipose tissue, as in liver, occurs as a result of activation of triglyceride lipase by phosphorylation. 

Figure 6.11 Interaction of adrenaline with the a-helices in the P2-adrenaline receptor which lead to a conformational change and activation of the coupled G-protein.

The term chiral recognition refers to a process m which some chiral receptor or reagent interacts selectively with one of the enantiomers of a chiral molecule Very high levels of chiral recognition are common m biological processes (—) Nicotine for exam pie IS much more toxic than (+) nicotine and (+) adrenaline is more active than (—) adrenaline m constricting blood vessels (—) Thyroxine an ammo acid of the thyroid gland that speeds up metabolism is one of the most widely used of all prescription... 

Heterologous desensitisation refers to the desensitisation of the response to one agonist by the application of a different agonist. For example, desensitisation of a response to adrenaline by application of 5-HT is mediated by protein kinase A or protein kinase C because these kinases can phosphorylate receptors which are not occupied by agonist. Phosphorylation disrupts the receptor-G-protein interaction and induces the binding of specific proteins, arrestins which enhance receptors internalisation via clathrin-coated pits. Thus desensitisation of G-protein-coupled receptors results in a decrease in the number of functional receptors on the cell surface. 

Higher differences for the interaction of both the biological and the synthetic receptors with the two enantiomers are found for the propanol-derivatives than for the ethanol-derivatives (Norephedrine, Metaraminol vs. Octopamime, Noradenaline Pseudoephedrine, Ephe-drine vs. Synephrine, Adrenaline). 

Although some steroids have been reported to reduce the toxic effects of some insecticides, the steroid ethylestrenol decreased the rate of recovery of depressed cholinesterase activity in disulfoton- pretreated rats (Robinson et al. 1978). The exact mechanism of this interaction was not determined. Ethylestrenol alone caused a small decrease in cholinesterase activity, and, therefore, resulted in an additive effect. Rats excreted less adrenaline and more noradrenaline when given simultaneous treatments of atropine and disulfoton compared with rats given disulfoton alone (Brzezinski 1973). The mechanism of action of disulfoton on catecholamine levels may depend on acetylcholine accumulation. In the presence of atropine, the acetylcholine effect on these receptors increases the ability of atropine to liberate catecholamines. 

In the sympathetic part of the peripheral autonomic nervous system the simation is less complicated since only the sympathetically innervated visceral organs have receptors sensitive to the transmitter of the postganglionic sympathetic neuron noradrenaline. However, the noradrenaline sensitive receptors, which all belong to the G-protein coupled receptor superfamily, can be subdivided in at least three subtypes ai-, a - and jSi-adrenoceptors. These receptors are to a similar extent sensitive to adrenaline, a humoral transmitter which is released under sympathetic control from the adrenal medulla. Adrenaline, in contrast to noradrenaline has affinity to a forth type, the /32-adrenoceptor. In general drug interacting with the autonomous nervous system can be subdivided according to their mechanism of action. 

The interaction of the Pycomplex with G-protein coupled receptor kinases (see 5.3.4, P-adrenergic receptor kinase, PARK) appears to be of special regulatory importance. The function of the Py-complex in this system is shown in Fig. 5.9. The Py-complex binds specifically to the PARK and translocates this to the cell membrane. The translocation of PARK is necessary to switch off and modulate signal transmission via adrenaline. 

When an asymmetric center is present in a compound, it is thought that the substituents on the chiral carbon atom make a three-point contact with the receptor. Such a fit insures a very specific molecular orientation which can only be obtained for one of the two isomers (Fig. 1.3). A three-point fit of this type was first suggested by Easson and Stedman [23], and the corresponding model proposed by Beckett [24] in the case of (R)-( )-adrenaline [= (R)-( )-epinephrine]. The more active natural (R)-( )-adrenaline establishes contacts with its receptor through the three interactions shown in Fig. 1.3. 

HA is synthesized from dietary histidine by the enzyme histidine decarboxylase (HDC). High levels of HDC activity are found in the stomach, either in mucosal mast cells or in ECL cells. Gastrin, Ach, and adrenaline interact with their respective receptors on the... 

Acceptor-donor or hydrophobic interaction between the aromatic ring of adrenaline and an aromatic ring of the receptor protein. 

Even in taking into account these newer findings, it can be speculated that the Easson-Stedman hypothesis still holds. The non-natural S(+)-adrenaline, having the wrong orientation of its benzylic hydroxyl, is unable to exchange a hydrogen bond with Ser , and achieves therefore a weaker interaction with the receptor. 

An alternative model of the adrenergic receptor-active site shows that natural R-( ) epinephrine (adrenaline) can establish a hydrogen bond with the Ser alcoholic group whereas this interaction is not possible with the non-natural S-(+) epinephrine (Eigure 26.3). 

Unlike TCAs, MAOIs do not interact with adrenaline or histamine receptors, so they present fewer sedative or jittery side effects than TCAs. However, MAOIs do have a serious risk factor associated with them. Specifically, when taken with certain foods they can cause a life-threatening hypertensive crisis. 

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