Adrenergic Agents. Adrenergic neurotransmitters. Structure and physicochemical properties

Transcription

1 Adrenergic Agents Adrenergic drugs are chemical agents that exert their principal pharmacological and therapeutic effects by either enhancing or reducing the activity of the various components of the sympathetic division of the autonomic nervous system. In general, substances that produce effects similar to stimulation of sympathetic nervous activity are known as sympathomimetics or adrenergic stimulants. Those that decrease sympathetic activity are referred to as sympatholytics, antiadrenergics, or adrenergic-blocking agents. Adrenergic drugs employed in the treatment of disorders of widely varying severity, include popular prescription drugs (such as albuterol for asthma and atenolol for hypertension), as well as many common TC cold remedies (such as the nasal decongestant pseudoephedrine). Adrenergic neurotransmitters Structure and physicochemical properties orepinephrine (E) is the neurotransmitter of the postganglionic sympathetic neuron. As a result of sympathetic nerve stimulation, it is released from sympathetic nerve endings into the synaptic cleft, where it interacts with specific presynaptic and postsynaptic adrenergic receptors. Another endogenous adrenergic receptor agonist is epinephrine. This compound is not release from peripheral sympathetic nerve endings, as is E. Rather, it is synthesized and stored 1

2 in the adrenal medulla, from which it is released into the circulation. Thus, epinephrine is often referred to as a neurohormone. Epinephrine is also biosynthesized in certain neurons of the CS, where both it and E serve as neurotransmitters. Epinephrine and E belong to the chemical class of substances known as the catecholamines. This name was given to these compounds because they contain an amino group attached to an aromatic ring that contains two hydroxyl groups situated ortho to each other, the same arrangement of hydroxyl groups as found in catechol. Aromatic compounds that contain such an arrangement of hydroxyl substituents are highly susceptible to oxidation. Catecholamines, such as epinephrine and E, undergo oxidation in the presence of oxygen or other oxidizing agents to produce ortho-quinone-like compounds, which undergo further reactions to give mixtures of colored products. ence, solutions of catecholamine drugs often are stabilized by addition of an antioxidant (reducing agent), such as ascorbic acid or sodium bisulfate. Biosynthesis, Storage and Release of orepinephrine Biosynthesis of norepinephrine takes place within adrenergic neurons near the terminus of the axon near the junction with the effector cell. The pathway for epinephrine biosynthesis in the adrenal medulla is the same as for norepinephrine with the additional step of conversion of norepinephrine to epinephrine by the enzyme phenylethanolamine--methyltransferase. This figure is biosynthesis of norepinephrine: 2

3 2 L-Tyrosine 2 Tyrosine hydroxylase 2 L-DPA Dopamine Aromatic L-amino acid decarboxylase Dopamine beta hydroxylase 2 within storage vesicle orepinephrine 3

4 Reuptake and metabolism of norepinephrine following release Following its release, norepinephrine diffuses through the intercellular space to bind reversibly to adrenoceptors (alpha or beta), on the effector cell, triggering a biochemical cascade that results in a physiologic response by the effector cell. In addition to the receptors on effector cells, there are also adrenoceptors that respond to E (α 2- receptors) on the presynaptic neuron, which, when stimulated by E, act to inhibit the release of additional E into the synapse. nce it has been released and is stimulating its various receptors, there must be mechanism for removing the E from the synapse and terminating the adrenergic impulse. By far the most important of these mechanisms for removing the E is transmitter recycling through active transport uptake into the presynaptic neuron. This process called uptake-1, is efficient, and in some tissues, up to 95% of released E is likely removed from the synapse by this mechanism. Part of the E taken into the presynaptic neuron by uptake-1 is metabolized to 3,4-dihydroxyphenylglycolaldehyde (DPGAL) by mitochondrial mono amine oxidase (MA), and part of it is sequestered in the storage vesicles to be used again as neurotransmitter. A less efficient uptake process, uptake-2, operates in a variety of other cell types but only in the presence of high concentrations of E. that portion of released E which escapes uptake-1 diffuses out of the synapse and is metabolized in extraneuronal sites by chatechol--methyltransferase, CMT, which methylates the meta hydroxyl group. E is also metabolized to DPGAL by MA present at extraneuronal sites, principally the liver and blood platelets. 4

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6 Effector Mechanisms of Adrenergic Receptors The receptors each are coupled through a G protein to effector mechanisms. Effector mechanisms are proteins that are able to translate the conformational change caused by activation of the receptor into a biochemical event within the cell. All of the beta adrenoceptors are coupled via specific G proteins to the activation of adenylyl cyclase. Thus, when the receptor is stimulated by an agonist, adenylyl cyclase is activated to catalyze the formation of cyclic-adenosine monophosphate (camp) from ATP. camp, called a second messenger for the beta adrenoceptors, is known to function as a second messenger for a number of other receptor types. camp is considered a messenger because it can diffuse through the cell for at least short distances to modulate biochemical events remote from the synaptic cleft. Modulation of biochemical events by camp includes a phosphorylation cascade of other proteins. camp is rapidly deactivated by hydrolysis of the phosphodiester bond by the enzyme phosphodiesterase. The α 2 - receptor may use more than one effector system depending on the location of the receptor. owever, to date the best understood effector system of the α 2 -receptor appears to be similar to that of the β-receptors except that linkage via a G protein leads to inhibition of adenylyl cyclase instead of activation. 6

7 2 2 P P P Adenylyl cyclase P ATP camp Phospho diesterase 2 3 P AMP The α 1 -adrenoceptor is linked through yet another G protein to a complex series of events involving hydrolysis of polyphosphatidylinositol. The first event set in motion by activation of the α 1 -receptor is activation of the enzyme phospholipase C. Phospholipase C catalyzes the hydrolysis of phosphatidylinositol biophosphate (PIP 2 ). This hydrolysis yields two products, each of which has biologic activity as second messengers of the α 1 -receptor. These are diacylglycerol (DAG) and inositol triphosphate (IP 3 ). IP 3 causes the release of calcium ions from intracellular storage sites in the endoplasmic reticulum resulting in an increase in 7

8 free intracellular calcium levels. Increased free intracellular calcium is correlated with smooth muscle contraction. DAG is thought to activate cytosolic protein kinase C, which may induce slowly developing contractions of vascular smooth muscle. The end result of a complex series of protein interactions triggered by agonist binding to the α 1 -receptor includes increased intracellular free calcium, which leads to smooth muscle contraction. When the smooth muscle innervated by α 1 -receptors is in vascular walls, stimulation leads to vascular contraction. Receptor Localization The generalization made in the past about synaptic locations of adrenoceptor subtypes was that all α 1, β 1, β 2 receptors are postsynaptic receptors that are linked to stimulation of biochemical processes in the postsynaptic cell. owever, presynaptic β-receptors are known to occur. The α 2 -receptor has been traditionally viewed as a presynaptic receptor that resides on the outer membrane of the nerve terminus or presynaptic cell and reacts with released neurotransmitter. The α 2 - receptor serves as a sensor and modulator of the quantity of neurotransmitter present in the synapse at any given moment. Thus, during periods of rapid nerve firing and neurotransmitter release, the α 2 -receptor is stimulated and causes an inhibition of further release of neurotransmitter. 8

9 Structure-Activity Relation Ships of Adrenergic Agonists (SARs) 3 / 2 / 1 2 R 1 R 3 4 / 5 / 6 / R2 Agents of this type have been extensively studied over the years since the discovery of the naturally occurring prototypes, epinephrine and norepinephrine, and the structural requirements and tolerances for substitutions at each of the indicated positions have been established. In general, a primary or secondary aliphatic amine separated by two carbons from a substituted benzene ring is minimally required for high agonist activity in this class. Because of the basic amino groups, pka range approximately 8.5 to 10, all of these agents are highly positively charged at physiologic p. By definition agents in this class have a hydroxyl group on Cl of the side chain, β to the amine, as in epinephrine and norepinephrine. This hydroxyl-substituted carbon must be in the R absolute configuration for maximal direct activity as in the natural neurotransmitter, although most drugs are currently sold as mixtures of both (R) and (S) stereoisomer s at this position (racemates). Given these features in common, the nature of the other substituents determines receptor selectivity and duration of action. In the following discussions, keep in mind that saying a drug is selective for a given receptor does not mean it has no activity at other receptors and that the clinically observed degree of selectivity is frequently dose-dependent. 9

10 R 1 substitution on the Amino itrogen We have already seen that as R1 is increased in size from hydrogen in norepinephrine to methyl in epinephrine to isopropyl in isoproterenol, activity at α- receptors decreases, and activity at β-receptors increases. These compounds were used to define alpha and beta activity long before receptor proteins could be isolated and characterized. The activity at both α and β- receptors is maximal when R1 is methyl as in epinephrine, but α-agonist activity is dramatically decrease when R1 is larger than methyl and is negligible when R1 is isopropyl as in isoproterenol, leaving only β-activity. In fact, the β-activity of isoproterenol is actually enhanced over norepinephrine and epinephrine. Presumably, the β- receptor has a large lipophilic binding pocket adjacent to the amine-binding aspartic acid residue, which is absent in the α-receptor. As R1 becomes larger than butyl, affinity for α1-receptors returns, but not intrinsic activity, which means large lipophilic groups can afford compounds with α1-blocking activity. In addition, the -substituent can also provide selectivity for different β-receptors, with a t-butyl group affording selectivity for β2-receptors. For example, with all other features of the molecules being constant, colterol is a selective β2-agonist, whereas isoproterenol is a non-selective β-agonist. When considering use as a bronchodilator, a non-selective β-agonist such as isoproterenol has undesirable cardiac stimulatory properties owing to its β1-activity that are greatly diminished in a selective β2-agonist. 10

11 Isoproterenol Colterol R2, Substitution α to the Basic itrogen (Carbon 2) Small alkyl groups, methyl or ethyl, may be present on the carbon adjacent to the amino nitrogen, carbon-2. Such substitution slows metabolism by (MA) but has little overall effect on duration of action in catecholamines because they remain substrates for catechol--methyltransferase (CMT). Resistance to MA activity is more important in noncatechol indirect acting phenylethylamines. An ethyl group in this position diminishes α activity far more than β-selectivity such as ethylnorepinephrine. R3, Substitution on the Aromatic Ring The natural 3, 4 dihydroxy substituted benzene ring present in norepinephrine provides excellent receptor activity for both α and β-sites, but such catechol-containing compounds have poor oral activity because they are hydrophilic and rapidly metabolized by CMT. Alternative substitutions have 11

12 been found that retain good activity but are more resistant to CMT metabolism. In particular, 3, 5 - dihydroxy compounds are not good substrates for CMT and, in addition, provide selectivity for β 2 -receptors. Thus, because of its ring substitution pattern, metaproterenol is an orally active bronchodilator having little of the cardiac stimulatory properties possessed by isoproterenol. Albuterol Metaproterenol ther substitutions are possible that enhance oral activity and provide selective β 2 activity, such as the 3 - hydroxymethyl, 4 -hydroxy substitution pattern of albuterol, which is also resistant to CMT. At least one of the groups must be capable of forming hydrogen bonds, and if there is only one, it should be at the 4 position to retain β-activity. For example Ritodrine has only a 4 - for R3, yet retains good β activity with the large substituent on the nitrogen making it β 2 selective. 12

13 C 3 Ritodrine If R3 is only a 3 -, however, activity is reduced at α sites and almost eliminated at β sites, thus affording selective α agonists such as phenylephrine and metaraminol. Further indication that alpha sites have a wider range of substituent tolerance for agonist activity is shown by the 2, 5 -dimethoxy substitution of methoxamine, which is a selective α-agonist that also has β-blocking activity at high concentrations. C 3 C C 3 C 3 Phenylephrine Metaraminol C 3 Methoxamine When the phenyl ring has no phenolic substituents, i.e., R3=, these phenylethanolamines may have both direct and indirect activity. Direct activity (i.e., agonist) is the stimulation of an adrenoceptor by the drug itself while indirect activity is the result of displacement of norepinephrine from its storage granules or reuptake inhibition resulting in non-selective stimulation of the adrenoceptors by the displaced norepinephrine. Since norepinephrine stimulates both α and β 1- adrenoceptors, indirect activity cannot be selective. 13

14 Endogenous Catecholamines The three naturally occurring catecholamines dopamine, E, and epinephrine are used as therapeutic agents. Dopamine is used in the treatment of shock. It is ineffective orally in large part because it is substrate for both MA and CMT. Thus, it is used intravenously. In contrast with the catecholamines E and epinephrine, dopamine increases blood flow to the kidney in doses that have no chronotropic effect on the heart or that cause no increase in blood pressure. The increased blood flow to the kidneys enhances glomerular filtration rate, a + excretion, and in turn, urinary output. The dilation of renal blood vessels produced by dopamine is the result of its agonist action on the D 1 -dopamine receptor. dopamine 2 In doses slightly higher than those required to increase renal blood flow, dopamine stimulates the β 1 -receptors of the heart to increase cardiac output. orepinephrine It is used to maintain blood pressure in acute hypotensive states resulting from surgical or nonsurgical trauma, central vasomotor depression, and hemorrhage. Like the other endogenous catecholamines, it is a substrate for both MA and CMT and thus is not effective by the oral route of administration. It is 14

15 given by intravenous injection. Sodium bisulfate is often used in preparation of E to protect it against oxidation. Epinephrine It finds use in a number of situations because of its potent stimulatory effects on both α and β-adrenergic receptors. Like the other catecholamines, epinephrine is light-sensitive and easily oxidized on exposure to air because of the catechol ring system. The development of a pink to brown color is indicative of oxidative breakdown. To minimize oxidation, solutions of the drug are stabilized by the addition of reducing agents such as sodium bisulfate. It is not effective by the oral route due to poor absorption and rapid metabolism by MA and CMT. Although IV infusion of epinephrine has pronounced effects on the cardiovascular system, its use in the treatment of heart block or circulatory collapse is limited because of its tendency to induce cardiac arrhythmias. It increases systolic pressure by increasing cardiac output, and it lowers diastolic pressure by causing an overall decrease in peripheral resistance; the net result is little change in mean blood pressure. Epinephrine is of value as a constrictor in hemorrhage or nasal congestion. 15

16 Dipivefrin It is the pivalic acid ester prodrug of epinephrine. It is formed by the esterification of the catechol hydroxyl groups of epinephrine with pivalic acid. Dipivefrin is much more lipophilic than epinephrine, and it achieves a much better penetration of the eye when administered topically as an aqueous solution for the treatment of primary open-angle glaucoma. It is epinephrine by esterases in the cornea and anterior chamber. Dipivefrin offers the advantage of being less irritating to the eye than epinephrine, and because of its more efficient transport into the eye, it can be used in lower concentrations than epinephrine. ( 3 C) 3 C C C 3 ( 3 C) 3 C C Dipivefrin Esterases Epinephrine + 2(C 3 ) 3 CC 2 16

17 Alpha-Adrenergic Receptor Agonists Phenylephrine is the prototypical selective direct-acting α1-receptor agonist. It is a potent vasoconstrictor and is active when given orally. It is metabolized by MA, but since it lacks the catechol moiety, it is not metabolized by CMT. It is relatively nontoxic and produces little CS stimulation. When applied to mucous membranes, it reduces congestion and swelling by constricting the blood vessels of the membranes. Thus, one of its main uses is in the relief of nasal congestion. In the eye, it is used to dilate the pupil and to treat open-angle glaucoma. It also is used in spinal anesthesia, to prolong the anesthesia and to prevent a drop in blood pressure during the procedure. Another selective direct-acting alpha1-receptor agonist used therapeutically is Methoxamine. This drug is a potent vasoconstrictor that has no stimulant action on the heart. In fact, it tends to slow the ventricular rate because of an activation of the carotid sinus reflex. It is used primarily during surgery to maintain adequate arterial blood pressure, especially in conjunction with spinal anesthesia. It does not stimulate the CS. 3 C 2 C 3 C 3 17

18 The naphazoline, tetrahydrozoline, xylometazoline, and oxymetazoline are partial agonists at both alpha1 and alpha 2 adrenergic receptors. These agents are used for their vasoconstrictive effects as nasal and ophthalmic decongestants. They have limited access to the CS since they essentially exist in an ionized form at physiological p because of the very basic nature of the imidazoline ring (pka = 9-10). R 18

19 aphazoline: R = C 2 Tetrahydrozoline R = 3 C xymetazoline: R = C 2 C(C 3 ) 3 3 C 3 C Xylometazoline R = C 2 C(C 3 ) 3 3 C 19

20 Clonidine: it is an example of a phenylimino imidazolidine derivative that possesses selectivity for the alpha 2 adrenergic receptor. Cl Cl Methyldopa (Aldomet) It is a close structural analogue of L-dopa, it is treated as an alternate substrate by the enzyme L-aromatic amino acid decarboxylase. The product of this initial enzymatic reaction is α-methyldopamine. This intermediate in turn is acted upon by dopamine β-hydroxylase to give the diastereoisomer of α- methylnorepinephrine, which possesses the (R)-configuration at the carbon with the β-hydroxyl group and the (S)-configuration at the carbon with the α-methyl substituent. Methyldopa is used only by oral administration since its zwitterionic character limits its solubility. 20

21 3 C 2 C 2 Methyldopa L-Aromatic Amino Acid Decarboxylase 3 C 2 alpha-methyl dopamine Dopamine Beta-hydroxylase 2 3 C alpha-methyl norepinephrine " METABLIC CVERSI F METYLDPA T ALPA- METYL REPIEPRIE" 21

22 β-adrenergic Receptor Agonists Isoproterenol is the prototypical β-adrenergic receptor agonist. Because of an isopropyl substitution on the nitrogen atom, it has virtually no effect on α- receptors. owever, it does act on both β 1 - and β 2 - receptors. It thus can produce an increase in cardiac output by stimulating cardiac β 1 -receptors and can bring about bronchodilation through stimulation of β 2 -receptors in the respiratory tract. Isoproterenol is available for use by inhalation, injection, and sublingual tablets. Its principal clinical use is for the relief of bronchospasms associated with bronchial asthma. The problems of lack of β-receptor selectivity and rapid metabolic inactivation associated with isoproterenol have been overcome at least partially by the design and development of a number of selective β 2 -adrenergic receptor agonists. These agents relax smooth muscle of the bronchi, uterus, and skeletal muscle vascular supply. They find their primary use as bronchodilators in the treatment of acute and chronic bronchial asthma and other obstructive pulmonary diseases. As pointed out in the discussion of SAR, modification of the catechol portion of a β-agonist has resulted in the development of selective β 2 -receptor agonists. For example metaproterenol and terbutaline(bricanyl) are resorcinol derivatives which are β 2 -selective. Although these agents have a lower affinity for β 2 -receptors than isoproterenol, they are much more effective when given orally and have a longer duration of action. This is because they are not metabolized by either MA or CMT. Instead, their metabolism primarily involves glucuronide conjugation. Although both metaproterenol and terbutaline 22

23 exhibit significant β 2 -receptor selectivity, the common cardiovascular effects associated with other adrenergic agents can also be seen with these drugs when high doses are used. Terbutaline Albuterol (Ventolin), pirbuterol and salmeterol are examples of selective β 2 -receptor agonists whose selectivity results from replacement of the meta-hydroxyl group of the catechol ring with a hydroxymethyl moiety. pirbuterol is closely related structurally to albuterol. The only difference between the two is that pirbuterol contains a pyridine ring instead of a benzene ring. As in the case of metaproterenol and terbutaline, these drugs are not metabolized by either CMT or MA. They thus are active orally and exhibit a much longer duration of action than isoproterenol. Salmeterol, in fact, is very long-acting (12 hours). 23

24 Pirbuterol Salmeterol Two additional sympathomimetic drugs that find use as bronchodilators are the α-ethyl catecholamines isoetharine and ethylnorepinephrine. Both of these are weaker than isoproterenol at stimulating β 2 -receptors. In addition, their β 2 -selectivity is not as great as that seen with drugs such as terbutaline or albuterol. Because of the presence of the α-ethyl group, isoetharine and ethylnorepinephrine are not metabolized by MA. owever, since both contain the catechol ring system, they are metabolized quite effectively by CMT and thus, their duration of action is similar to that seen with isoproterenol. 24

25 R 3 C ethylnorepinephrine: R= isoetharine : R=C(C 3 ) 2 Bitolterol It is a prodrug of the β 2 -selective adrenergic agonist colterol, the -tert-butyl analogue of E. The presence of the two p-toluic acid esters in bitolterol makes it considerably more lipophilic than colterol. Bitolterol is administered by inhalation for bronchial asthma and reversible bronchospasm. 25

26 Bitolterol C 2 C(C 3 ) C 3 Colterol p-toluic acid 26

27 Ritodrine: is a selective β 2 -selective agonist used to control premature labor and to reverse fetal distress caused by excessive uterine activity. Its uterine inhibitory effects are more sustained than its effects on the cardiovascular system, which are minimal compared with those caused by nonselective β-agonists. Dobutamine Dobutamine is a dopamine analog with a bulky arylalkyl group on the nitrogen and one chiral (asymmetric) center. Racemic dobutamine has direct activity on both α 1 and β 1 -receptors, but because of some unusual properties of its two enantiomers, the overall pharmacologic response looks similar to that of a selective β 1 -agonist. The S(-)-isomer of dobutamine exhibits β 1 -agonist activity and also is a powerful α 1 -agonist and vasopressor. The R(+)-isomer is an α 1 - antagonist; thus, when the racemate is used clinically, the α-effects of the enantiomers cancel each other leaving primarily the β 1 -effects. The stereochemistry of the methyl substituent does not affect the ability of the drug to bind to the α 1 - receptor but does affect the ability of the molecule to activate the receptor. That is, the stereochemistry of the methyl group affects intrinsic activity but not affinity. Because both stereoisomers are β 1 -agonists with the (+)-isomer about 1/10 the 27

28 potency of the (-)-isomer, the net effect is β 1 -stimulation. Dobutamine is used as a cardiac stimulant after surgery or congestive heart failure. As a catechol, dobutamine is readily metabolized by CMT and has a short duration of action with no oral activity. 28

29 Indirect Acting Sympathomimetics It act by releasing endogenous E. Indirect acting drugs that are used therapeutically are not catechol derivatives and in most cases do not even contain a hydroxyl moiety. in contrast with the direct acting agents, the presence of a β- hydroxyl group decreases, and an α-methyl group increases, the effectiveness of indirect-acting agents. The presence of nitrogen substituents decreases indirect activity, with substituents larger than methyl rendering the compound virtually inactive. Phenylethylamines that contain a tertiary amino group are also ineffective as E-releasing agents. Given the foregoing structure-activity considerations, it is easy to understand why amphetamine and p-tyramine are often cited as prototypical indirect-acting sympathomimetics. Since amphetamine type drugs exert their primary effects on the CS. Amphetamine and methamphetamine cause dramatic central nervous system stimulation, which gives them serious abuse potential. They have central appetite suppressant effects C Amphetamine p-tyramine 29

30 L-(+) Pseudoephedrine Is the (S,S)-diastereoisomer of ephedrine. Whereas ephedrine has a mixed mechanism of action, Pseudoephedrine acts by an indirect mechanism. The structural basis for this difference in mechanism is the stereochemistry of the carbon atom possessing the β-hydroxyl group. In pseudoephedrine, this carbon atom possesses the (S)-configuration, which is the wrong stereochemistry at this center for a direct-acting effect at adrenergic receptors. This agent is found in many over-the-counter preparations used as nasal decongestants. Although it is less prone to increase blood pressure than ephedrine, it should be used with caution in hypertensive individuals. S S C 3 C 3 L-(+)-Pseudoephedrine 30