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Adrenergic (Sympathomimetic) Drugs
Chapter 11
Adrenergic (Sympathomimetic) Drugs Adrenaline is a hormone produced within the adrenal gland in response to stress that increases heart rate, strengthens the force of the heart’s contraction and cardiac output, increases blood pressure and opens up the bronchioles in the lungs, and raises the blood levels of glucose and lipids among other effects. The secretion of adrenaline is a part of the human “fight or flight” response, the acute stress response to fear, perceived threat, or panic. An excessive adrenaline level usually is observed in highly emotional and overaggressive persons. On the other hand, there are some disorders of the adrenal glands that reduce the level of epinephrine to below normal, including Addison disease and other forms of hypoadrenalism. Any drug that mimics the functioning of the sympathetic nervous system by affecting the release or action of epinephrine (adrenaline) (11.1), norepinephrine (noradrenaline) (11.2), and dopamine (11.3)—hormones that are secreted by the adrenal gland—is considered an adrenergic drug. The term adrenergic literally means “having to do with adrenaline (epinephrine) and/or noradrenaline (norepinephrine)” [1,2] (Fig. 11.1.). The main function of the mentioned hormones is to adapt the body to stressful situations and they have a half-life of a few minutes when circulating in the blood. They undergo degradation either by catechol-O-methyltransferases or by monoamine oxidases.
FIG. 11.1 Structure of epinephrine, norepinephrine and dopamine.
By definition, adrenergic agonists produce their effects by activating adrenergic receptors. There are at least two adrenergic receptor types—α and β (α1, α2, β1, and β2 receptors)—by which adrenergic drugs exert their effects. Norepinephrine activates primarily α and epinephrine activates primarily β receptors, although epinephrine may also activate α receptors. Stimulation of α receptors is associated Synthesis of Best-Seller Drugs. http://dx.doi.org/10.1016/B978-0-12-411492-0.00011-0 Copyright © 2016 Elsevier B.V. All rights reserved.
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with constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract. β-Receptor activation relaxes bronchial smooth muscles, which causes the bronchi to dilate, causing an increase in the rate and force of heart contractions. Adrenergic agonists (sympathomimetic agents) raise blood pressure and increase heart rate. Therapeutically, these drugs are used to provide patients relief from disorders such as bronchial asthma, chronic obstructive pulmonary diseases, cardiac arrest, allergic reactions, and nasal decongestants; they are also used as appetite suppressants. Adrenergic drugs increase the output of the heart, and used to be given as heart stimulants to raise blood pressure, reversing the drop in blood pressure, and to increase urine flow as part of the treatment of shock. They also may be used to stop bleeding by causing the blood vessels to constrict. Adrenergic agonists are subdivided into three classes: direct acting, indirect acting, and dual acting. 1. Direct-acting agonists bind to and activate α1, α2, β1, and β2 receptors. Naturally occurring molecules that bind to these receptors include epinephrine (11.1), which binds to α1,α2, and β1 receptors, norepinephrine (11.2), which binds to α1, α2, and β1 receptors, and dopamine (11.3), which binds to dopamine receptors as well as to α1 and β1 receptors. Direct-acting agonists such as isoproterenol (11.4), dobutamine (11.5), phenylephrine (11.6), and clonidine (11.7) (Fig. 11.2.), are also adrenergic drugs.
FIG. 11.2 Direct-acting adrenergic agonists.
2. Indirect-acting adrenergic agonists produce norepinephrine-like actions by stimulating norepinephrine release. Amphetamines—(amphetamine (11.8), methylamphetamine (11.9), hydroxy amphetamine (11.10), tyramine (11.11)) (Fig. 11.3.), prevent its reuptake. Tricyclic antidepressant (amitriptyline (11.12), cocaine (11.13)), which acts by multiple mechanisms on brain catecholaminergic neurons and compounds inhibiting of norepinephrine inactivation (monoamine oxidase [MAO] inhibitors) increase the amount of norepinephrine available for release.
FIG. 11.3 Indirect acting adrenergic agonists.
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3. Dual-acting adrenergic agonists, which bind to adrenergic receptors and stimulate norepinephrine release. Among them are drugs such as ephedrine (11.14) and metaraminol (11.15) (Fig. 11.4.).
FIG. 11.4 Dual-acting adrenergic agonists.
According to their chemical structure, sympathomimetic drugs may be divided into catecholamines and noncatecholamines. Catecholamines are hormones produced by the adrenal glands. It is a group of sympathomimetic amines (including dopamine, epinephrine, and norepinephrine), the aromatic constituent of whose molecules is catechol (o-dihydroxybenzene). Noncatecholamines used as adrenomimetics are phenylephrine (11.6), amphetamine (11.8), methylamphetamine (11.9), hydroxyamphetamine (11.10), tyramine (11.11), and ephedrine (11.14). Because they lack a catechol group, noncatecholamines are not substrates for metabolizing enzymes. As a result, their half-lives are much longer than those of catecholamines, they can be given to a patient orally, and they are more able to cross the blood– brain barrier. The receptor mediating the vasoconstrictor actions of catecholamines is referred to as an α receptor. α Receptors are associated mainly with increased contractibility of vascular smooth muscle and intestinal relaxation. α Receptors have been further subdivided into α1 and α2 receptors. Epinephrine and norepinephrine activate both receptors.
11.1 α1-RECEPTOR ACTIVATING DRUGS α1 Receptors are characteristic of vascular smooth muscle, although their density varies throughout the body—eye, skin, viscera, mucous membranes, veins, sex organs, and bladder—but are quite abundant on blood vessels of the oral and nasal mucosae and urinary sphincters. α1 Receptors are also found on muscles attached to hair follicles. Their contraction accounts for “goose bumps.” They are also found on apocrine sweat glands in the armpits, groin, and palms, causing “nervous sweat” solely as a result of the hormones in the blood. Contraction of the dilator muscle of the iris is caused by α1 binding, which causes the pupil to dilate and can facilitate eye examinations and ocular surgery. Dilator muscle contraction is the only clinical use of α1 activation that is not based on vasoconstriction. Activation of α1 receptors elicits two responses that can be of therapeutic use: vasoconstriction and mydriasis. Vasoconstriction is the one for which α1 agonists are used most often.
192 Synthesis of Best-Seller Drugs
Because of their properties as vasoconstrictive agents, α1 agonists are used to reduce edema and inflammation. They are used to stop bleeding primarily in the skin and mucous membranes, and as nasal decongestants. α1-Agonists are frequently combined with local anesthetics to delay anesthetic absorption. Common α1-receptor activating drugs include phenylephrine (11.6), pseudoephedrine (11.1.1), methoxamine (11.1.2), and propylhexedrine (11.1.3), which are based on the phenylethylamine skeleton, and dihydroimidazole derivatives such as naphazoline (11.1.4), tetrahydrozoline (11.1.5), xylometazoline (11.1.6), oxymetazoline (11.1.7), and cirazoline (11.1.8) (Fig. 11.5.)
FIG. 11.5 α1-Receptor activating drugs.
α1-Receptor activating drugs are used for temporary relief of congestion in the nose caused by various conditions, including the common cold, sinusitis, hay fever, and allergies, and to relieve redness, puffiness, and itchy/watering eyes resulting from colds, allergies, or an eye irritation. α1-Agonists can cause headache, reflex bradycardia, excitability, and restlessness.
11.2 α2-RECEPTOR ACTIVATING DRUGS α2 Receptors are located in presynaptic nerve terminal. In the periphery, they are mainly located on vascular smooth muscle of veins, more so than on arteries. They are abundant in the brain and are associated with the pain perception. Activation of these receptors inhibits the release of norepinephrine. There are no therapeutic applications related to activation of peripheral α2 receptors. In contrast, activation of α2 receptors in the central nervous system (CNS) are of great clinical significance, producing two useful effects: reduction of sympathetic outflow to the heart and blood vessels and relief of severe pain. Several α2 selective adrenergic agonists are known: methylepinephrine (11.2.1), α-methylnorepinephrine (11.2.2), clonidine (11.2.3), tizanidine (11.2.4), guanabenz (11.2.5), guanfacine (11.2.6), and guanethidine (11.2.7) (Fig. 11.6.).
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FIG. 11.6 α2 Receptor agonists.
The α2-adrenoceptor agonists are used very occasionally as centrally acting hypotensive agents. Side effects of centrally acting α2-adrenoceptor agonists include sedation, dry mouth and nasal mucosa, bradycardia, orthostatic hypotension, and impotence.
11.3 β1-RECEPTOR ACTIVATING DRUGS β1-Receptor locations are heart muscle and kidney. These receptors are associated with the conducting system (e.g., pacemaker) and the ventricular musculature. They are also found in eccrine sweat and salivary glands. Epinephrine (11.1.1) or norepinephrine (11.1.2) causes excitatory responses in these tissues. Activation of β1 receptors in the heart has a positive inotropic effect by increasing the force of contraction, thereby improving cardiac performance. The primary goal of treatment with β1 agonists is to maintain blood flow to vital organs. By activating cardiac β1 receptors, drugs can initiate contraction in a heart that has stopped beating. Selective β1-activating drugs are dobutamine (11.5), denopamine (11.3.1), prenalterol (11.3.2), and xamoterol (11.3.3), which is considered third-generation β-adrenergic receptor partial agonist that provides cardiac stimulation at rest, but acts as a β blocker during exercise (Fig. 11.7.).
FIG. 11.7 β1 Receptor agonists.
Drugs that activate the β1 receptor are used in heart failure to improve the contractile state of the failing heart. They also increase heart rate, but excess stimulation can induce significant increases in heart rate and arrhythmias
11.4 β2-RECEPTOR ACTIVATING DRUGS β2 Receptors are found in bronchial smooth muscle and blood vessels of skeletal muscle, arterioles, heart, lung, uterus, and liver. Therapeutic applications of β2 activation are limited to the lungs and the uterus. Because drugs that activate β2
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receptors cause smooth muscle relaxation in the lung promoting bronchodilation and help relieve or prevent asthma attacks, β2 agonists are used for treatment of airways dysfunction such as bronchial asthma, chronic bronchitis, and emphysema, and in cases of premature labor for relaxing uterine smooth muscle. Drugs used for their β2-activating ability also can be classified as shortacting— albuterol (11.4.1), pirbuterol (11.4.2), procaterol (11.4.3), orciprenaline (11.4.5), terbutaline (11.4.6), fenoterol (11.4.7), and isoprenaline (11.4.8)—and long-acting— formoterol (11.4.9), bambuterol (11.4.10), clenbuterol (11.4.11), and salmeterol (11.4.12)—drugs (Fig. 11.8.).
FIG. 11.8 β2 Receptor agonists.
Most side effects of β2 agonists result from their concurrent β1 activity and include an increase in heart rate, a rise in systolic pressure, a decrease in diastolic pressure, chest pain, and arrhythmia.
11.5 DOPAMINE-RECEPTOR ACTIVATING DRUGS Dopamine receptors are involved in many neurological functions, such as motivation, memory, motor control, endocrine signaling. Dysfunction of dopaminergic neurotransmission in the CNS could be a reason of some neuropsychiatric disorders. There are at least five subtypes of dopamine receptors, D1 to D5. Some dopamine agonists can treat the hypodopaminergic state of organism, which is viewed as one of the main causes that triggers drug-seeking and taking; they are typically used for relieving Parkinson disease symptoms and restless legs syndrome.
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Activation of peripheral dopamine receptors causes dilation of the renal vasculature. This effect is exploited in the treatment of shock: by dilating renal blood vessels, renal perfusion is improved, thereby reducing the risk of renal failure. Dopamine itself is a drug that can activate dopamine receptors. It should be noted that, when dopamine is given to treat shock, the drug also enhances cardiac performance (because it activates β1 receptors in the heart). Common dopamine receptor agonists are dopamine (11.3) itself, apomorphine (11.5.1), bromocriptine (11.5.2), cabergoline (11.5.3), lisuride (11.5.4), pergolide (11.5.5), pramipexole (11.5.6), ropinirole (11.5.7), rotigotine (11.5.8), ciladopa (11.5.9), and derivatives of hexidine, namely, dihydrexidine (11.5.10), dinapsoline (11.5.11), and dinoxyline (11.5.12) (Fig. 11.9.).
FIG. 11.9 Dopamine receptor agonists.
11.6 MULTIPLE ADRENORECEPTOR ACTIVATION Anaphylactic shock is a manifestation of severe allergy. The reaction is characterized by hypotension (from widespread vasodilation), bronchoconstriction, and edema of the glottis. Epinephrine (11.1), is the treatment of choice for anaphylactic shock. Benefits derive from activating three types of adrenergic receptors: α1, β1, and β2. By activating these receptors, epinephrine can reverse the most-severe manifestations of the anaphylactic reaction. Activation of β1 receptors increases cardiac output, thereby helping elevate blood pressure. Blood pressure is also increased because epinephrine promotes α1-mediated vasoconstriction. In addition to increasing blood pressure, vasoconstriction helps
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suppress glottal edema. By activating β2 receptors, epinephrine can counteract bronchoconstriction. Mixed-acting drugs are epinephrine (11.1), norepinephrine (11.2), dobutamine (11.5), ephedrine (11.14), pseudoephedrine (11.1.1), and amphetamine (11.8). Synthesis of the most of the discussed drugs is described in our previous book [3].
11.7 DOPAMINE-RECEPTOR AGONIST BESTSELLER DRUGS On the list of Top 200 Drugs by sales for the 2010s are Guanfacine–Intuniv (11.2.5) and Albuterol (Salbutamol)–Ventolin (11.4.1)
Guanfacine–Intuniv Guanfacine is a classic, centrally acting antihypertensive known to stimulate central α2-adrenoceptors, which induces peripheral sympathoinhibition and hence reduces elevated blood pressure, predominantly as a result of vasodilation and a consequent decrease in peripheral vascular resistance. Its antihypertensive efficacy is beyond doubt, but the profile of adverse reactions is considered unfavorable [4,5]. Possible adverse reactions include blurred vision, confusion, dizziness, sweating, unusual tiredness, and weakness. Nevertheless guanfacine is one of the bestselling drugs for reducing high blood pressure. Moreover, after the discovery that the prefrontal cortex, which regulates behavior, thought, and emotion, is among the most evolved brain regions and that many cognitive disorders involve impairment of the prefrontal cortex [6], guanfacine was found to be capable of managing attention deficit hyperactivity disorder [7,8]. The synthesis of guanfacine is pretty simple and consists of an interaction of 2,6-dichlorophenylacetyl chloride or ethyl 2,6-dichlorophenyl acetate (11.7.1) with guanidine [9]. An alternate synthesis proposed by the same authors includes formylation of 2,6-dichlorophenylbenzyl cyanide (11.7.2) with ethyl formate to prepare a formylphenylacetonitrile derivative (11.7.3), which, after condensation with guanidine, produced (11.7.4), which was hydrated using hydrochloric acid to produce the desired guanfacine (11.2.5) [10,11] (Scheme 11.1.).
SCHEME 11.1 Synthesis of guanfacine.
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Albuterol–Salbutamol Albuterol is a short-acting β2-adrenergic receptor agonist and for more than 25 years was used to relieve bronchospasms in conditions such as asthma, bronchospasm, and other obstructive pulmonary diseases. Its side effects include restlessness, irritability, nervousness, sometimes tremor, and increased or irregular heart rate [12-14]. The two general methods for the synthesis of albuterol are based on two starting materials: substituted benzophenones and salicylic acid derivatives. The general approach started from 4-hydroxyacetophenone is described as follows [15] (Scheme 11.2.): 4-Hydroxyacetophenone (11.7.5) Blanc chloromethylation using formaldehyde and hydrogen chloride produces 4-hydroxy-3-chloromethylyacetophenone (11.7.6), which was acylated with a mixture of acetic anhydride, acetic acid, and sodium acetate to yield ketone (11.7.7). Bromination of the obtained ketone produces bromoketone (11.7.8), which on reaction with N-benzyl-N-t-butyl amine produces the aminoketone (11.7.9). After hydrolysis of acetyl groups with hydrochloric acid, the keto group in the diol (11.7.10) was reduced with sodium borohydride to give the triol (11.7.11). The triol was debenzylated with hydrogen using a Pd-C catalyst to produce the desired albuterol (11.4.1). Different modifications of this general approach have been proposed [16-22].
SCHEME 11.2 Synthesis of albuterol.
An approach started from methyl salicylate is outlined in Scheme 11.3 [16,17]. Methyl salicylate (11.7.12) was acylated with bromoacetyl chloride and the obtained bromoketone (11.7.13), on reaction with N-benzyl-N-t-butyl amine, produced aminoketone (11.7.14). Hydrogenation of the aminoketone with lithium aluminium hydride produced the known triol (11.7.11), which on debenzylation with hydrogen by Pd-C catalyst produced the desired albuterol (11.4.1).
SCHEME 11.3 Synthesis of albuterol.
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The details for both methods are discussed in the review [18]. The two enantiomers of the drugs are usually found to have significantly different potencies, but in the case of albuterol, effects of (R)-albuterol compared with (R,S)-albuterol, which have been documented in various cells and in vivo animal models, remain controversial [19-22].
REFERENCES 1. Brunton, L.; Lazo, J. S.; Parker, K.; Goodman, L. S.; Gilman, A. G. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, 2006. 2. Lemke, T. L.; David, A.; Williams, D. A. Foye’s Principles of Medicinal Chemistry, 6th ed.; Lippincott Williams & Wilkins, 2008. 3. Vardanyan, R. S.; Hruby, V. J. Synthesis of Essential Drugs; Elsevier, 2006. 4. Scholtysik, G.; Jerie, P.; Picard, C. W. Guanfacine. In Pharmacology of Antihypertension Drugs; Scriabine, A., Ed.; Raven Press, 1980; pp 79–98. 5. Scholtysik, G.; Fetkovska, N. Pharmacology of guanfacine. Cor Vasa 1987, 29 (4 Suppl. 1), S11–S16. 6. Arnsten, A. F. T.; Jin, L. E. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J. Biol. Med. 2012, 85 (1), 45–58. 7. Posey, D. J.; McDougle, C. J. Guanfacine and guanfacine extended release: treatment for ADHD and related disorders. CNS Drug Rev. 2007, 13 (4), 465–474. 8. Bukstein, O. G.; Head, J. Guanfacine ER for the treatment of adolescent attention-deficit/ hyperactivity disorder. Expert Opin. Pharmacother. 2012, 13 (15), 2207–2213. 9. Bream, J. B.; Picard, C. W. Acetylguanidine derivatives, FR 1584670 (1969). 10. Bream, J. B.; Picard, C. W. Phenylacetylguanidines, CH511816 (1971). 11. Bream, J. B.; Lauener, H.; Picard, C. W.; Scholtysik, G.; White, T. G. Substituted phenylacetylguanidines, a new class of antihypertensive agents. Arzneim. Forsch. 1975, 25 (10), 1477–1482. 12. Ahrens, R. C.; Smith, G. D. Albuterol: an adrenergic agent for use in the treatment of asthma. Pharmacology, pharmacokinetics and clinical use, Pharmacotherapy 1984, 4 (3), 105–121. 13. Price, A. H.; Clissold, S. P. Salbutamol in the 1980s. A reappraisal of its clinical efficacy, Drugs 1989, 38 (1), 77–122. 14. Colice, G. L. Albuterol HFA for the management of obstructive airway disease. Expert Rev. Respir. Med. 2008, 2 (2), 149–159. 15. Lunts, L. H. C.; Toon, P. Hydroxy-αγ-(aminomethyl)-m-xylene-α’,α3-diols as stimulators, US 3644353 (1972). 16. Lunts, L. H. C.; Toon, P. 1-Phenyl-2-aminoethanol derivatives as bronchodilators, US 3705233 (1972). 17. Collin, D. T.; Hartley, D.; Jack, D.; Lunts, L. H. C.; Press, J. C.; Ritchie, A. C.; Toon, P. Saligenin analogs of sympathomimetic catechol amines. J. Med. Chem. 1970, 13 (4), 674–680. 18. Skachilova, S. Y.; Zueva, E. F.; Muravskaya, I. D.; Goncharenko, L. V.; Smirnov, L. D. Procedures for preparing salbutamol (a review). Khim.-Farm. Zh. 1991, 25 (10), 59–65. 19. Hartley, D.; Middlemiss, D. Absolute configuration of the optical isomers of salbutamol. J. Med. Chem. 1971, 14 (9), 895–896.
Adrenergic (Sympathomimetic) Drugs Chapter | 11 199 20. Hawkins, C. J.; Klease, G. T. Relative potency of (-)- and (plus-)-salbutamol on guinea pig tracheal tissue. J. Med. Chem. 1973, 16 (7), 856–857. 21. Bakale, R. P. The development of routes to (R)-albuterol hydrochloride. Spec. Chem. 1995, 15 (6), 249–250. 253. 22. Barnes, P. J. Treatment with (R)- albuterol has no advantage over racemic albuterol. Rebuttal by Dr. Barnes, Am. J. Respir. Crit. Care Med. 2006, 174 (9), 974.
Adrenergic (Sympathomimetic) Drugs Adrenaline is a hormone produced within the adrenal gland in response to stress that increases heart rate, strengthens the force of the heart’s contraction and cardiac output, increases blood pressure and opens up the bronchioles in the lungs, and raises the blood levels of glucose and lipids among other effects. The secretion of adrenaline is a part of the human “fight or flight” response, the acute stress response to fear, perceived threat, or panic. An excessive adrenaline level usually is observed in highly emotional and overaggressive persons. On the other hand, there are some disorders of the adrenal glands that reduce the level of epinephrine to below normal, including Addison disease and other forms of hypoadrenalism. Any drug that mimics the functioning of the sympathetic nervous system by affecting the release or action of epinephrine (adrenaline) (11.1), norepinephrine (noradrenaline) (11.2), and dopamine (11.3)—hormones that are secreted by the adrenal gland—is considered an adrenergic drug. The term adrenergic literally means “having to do with adrenaline (epinephrine) and/or noradrenaline (norepinephrine)” [1,2] (Fig. 11.1.). The main function of the mentioned hormones is to adapt the body to stressful situations and they have a half-life of a few minutes when circulating in the blood. They undergo degradation either by catechol-O-methyltransferases or by monoamine oxidases.
FIG. 11.1 Structure of epinephrine, norepinephrine and dopamine.
By definition, adrenergic agonists produce their effects by activating adrenergic receptors. There are at least two adrenergic receptor types—α and β (α1, α2, β1, and β2 receptors)—by which adrenergic drugs exert their effects. Norepinephrine activates primarily α and epinephrine activates primarily β receptors, although epinephrine may also activate α receptors. Stimulation of α receptors is associated Synthesis of Best-Seller Drugs. http://dx.doi.org/10.1016/B978-0-12-411492-0.00011-0 Copyright © 2016 Elsevier B.V. All rights reserved.
189
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with constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract. β-Receptor activation relaxes bronchial smooth muscles, which causes the bronchi to dilate, causing an increase in the rate and force of heart contractions. Adrenergic agonists (sympathomimetic agents) raise blood pressure and increase heart rate. Therapeutically, these drugs are used to provide patients relief from disorders such as bronchial asthma, chronic obstructive pulmonary diseases, cardiac arrest, allergic reactions, and nasal decongestants; they are also used as appetite suppressants. Adrenergic drugs increase the output of the heart, and used to be given as heart stimulants to raise blood pressure, reversing the drop in blood pressure, and to increase urine flow as part of the treatment of shock. They also may be used to stop bleeding by causing the blood vessels to constrict. Adrenergic agonists are subdivided into three classes: direct acting, indirect acting, and dual acting. 1. Direct-acting agonists bind to and activate α1, α2, β1, and β2 receptors. Naturally occurring molecules that bind to these receptors include epinephrine (11.1), which binds to α1,α2, and β1 receptors, norepinephrine (11.2), which binds to α1, α2, and β1 receptors, and dopamine (11.3), which binds to dopamine receptors as well as to α1 and β1 receptors. Direct-acting agonists such as isoproterenol (11.4), dobutamine (11.5), phenylephrine (11.6), and clonidine (11.7) (Fig. 11.2.), are also adrenergic drugs.
FIG. 11.2 Direct-acting adrenergic agonists.
2. Indirect-acting adrenergic agonists produce norepinephrine-like actions by stimulating norepinephrine release. Amphetamines—(amphetamine (11.8), methylamphetamine (11.9), hydroxy amphetamine (11.10), tyramine (11.11)) (Fig. 11.3.), prevent its reuptake. Tricyclic antidepressant (amitriptyline (11.12), cocaine (11.13)), which acts by multiple mechanisms on brain catecholaminergic neurons and compounds inhibiting of norepinephrine inactivation (monoamine oxidase [MAO] inhibitors) increase the amount of norepinephrine available for release.
FIG. 11.3 Indirect acting adrenergic agonists.
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3. Dual-acting adrenergic agonists, which bind to adrenergic receptors and stimulate norepinephrine release. Among them are drugs such as ephedrine (11.14) and metaraminol (11.15) (Fig. 11.4.).
FIG. 11.4 Dual-acting adrenergic agonists.
According to their chemical structure, sympathomimetic drugs may be divided into catecholamines and noncatecholamines. Catecholamines are hormones produced by the adrenal glands. It is a group of sympathomimetic amines (including dopamine, epinephrine, and norepinephrine), the aromatic constituent of whose molecules is catechol (o-dihydroxybenzene). Noncatecholamines used as adrenomimetics are phenylephrine (11.6), amphetamine (11.8), methylamphetamine (11.9), hydroxyamphetamine (11.10), tyramine (11.11), and ephedrine (11.14). Because they lack a catechol group, noncatecholamines are not substrates for metabolizing enzymes. As a result, their half-lives are much longer than those of catecholamines, they can be given to a patient orally, and they are more able to cross the blood– brain barrier. The receptor mediating the vasoconstrictor actions of catecholamines is referred to as an α receptor. α Receptors are associated mainly with increased contractibility of vascular smooth muscle and intestinal relaxation. α Receptors have been further subdivided into α1 and α2 receptors. Epinephrine and norepinephrine activate both receptors.
11.1 α1-RECEPTOR ACTIVATING DRUGS α1 Receptors are characteristic of vascular smooth muscle, although their density varies throughout the body—eye, skin, viscera, mucous membranes, veins, sex organs, and bladder—but are quite abundant on blood vessels of the oral and nasal mucosae and urinary sphincters. α1 Receptors are also found on muscles attached to hair follicles. Their contraction accounts for “goose bumps.” They are also found on apocrine sweat glands in the armpits, groin, and palms, causing “nervous sweat” solely as a result of the hormones in the blood. Contraction of the dilator muscle of the iris is caused by α1 binding, which causes the pupil to dilate and can facilitate eye examinations and ocular surgery. Dilator muscle contraction is the only clinical use of α1 activation that is not based on vasoconstriction. Activation of α1 receptors elicits two responses that can be of therapeutic use: vasoconstriction and mydriasis. Vasoconstriction is the one for which α1 agonists are used most often.
192 Synthesis of Best-Seller Drugs
Because of their properties as vasoconstrictive agents, α1 agonists are used to reduce edema and inflammation. They are used to stop bleeding primarily in the skin and mucous membranes, and as nasal decongestants. α1-Agonists are frequently combined with local anesthetics to delay anesthetic absorption. Common α1-receptor activating drugs include phenylephrine (11.6), pseudoephedrine (11.1.1), methoxamine (11.1.2), and propylhexedrine (11.1.3), which are based on the phenylethylamine skeleton, and dihydroimidazole derivatives such as naphazoline (11.1.4), tetrahydrozoline (11.1.5), xylometazoline (11.1.6), oxymetazoline (11.1.7), and cirazoline (11.1.8) (Fig. 11.5.)
FIG. 11.5 α1-Receptor activating drugs.
α1-Receptor activating drugs are used for temporary relief of congestion in the nose caused by various conditions, including the common cold, sinusitis, hay fever, and allergies, and to relieve redness, puffiness, and itchy/watering eyes resulting from colds, allergies, or an eye irritation. α1-Agonists can cause headache, reflex bradycardia, excitability, and restlessness.
11.2 α2-RECEPTOR ACTIVATING DRUGS α2 Receptors are located in presynaptic nerve terminal. In the periphery, they are mainly located on vascular smooth muscle of veins, more so than on arteries. They are abundant in the brain and are associated with the pain perception. Activation of these receptors inhibits the release of norepinephrine. There are no therapeutic applications related to activation of peripheral α2 receptors. In contrast, activation of α2 receptors in the central nervous system (CNS) are of great clinical significance, producing two useful effects: reduction of sympathetic outflow to the heart and blood vessels and relief of severe pain. Several α2 selective adrenergic agonists are known: methylepinephrine (11.2.1), α-methylnorepinephrine (11.2.2), clonidine (11.2.3), tizanidine (11.2.4), guanabenz (11.2.5), guanfacine (11.2.6), and guanethidine (11.2.7) (Fig. 11.6.).
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FIG. 11.6 α2 Receptor agonists.
The α2-adrenoceptor agonists are used very occasionally as centrally acting hypotensive agents. Side effects of centrally acting α2-adrenoceptor agonists include sedation, dry mouth and nasal mucosa, bradycardia, orthostatic hypotension, and impotence.
11.3 β1-RECEPTOR ACTIVATING DRUGS β1-Receptor locations are heart muscle and kidney. These receptors are associated with the conducting system (e.g., pacemaker) and the ventricular musculature. They are also found in eccrine sweat and salivary glands. Epinephrine (11.1.1) or norepinephrine (11.1.2) causes excitatory responses in these tissues. Activation of β1 receptors in the heart has a positive inotropic effect by increasing the force of contraction, thereby improving cardiac performance. The primary goal of treatment with β1 agonists is to maintain blood flow to vital organs. By activating cardiac β1 receptors, drugs can initiate contraction in a heart that has stopped beating. Selective β1-activating drugs are dobutamine (11.5), denopamine (11.3.1), prenalterol (11.3.2), and xamoterol (11.3.3), which is considered third-generation β-adrenergic receptor partial agonist that provides cardiac stimulation at rest, but acts as a β blocker during exercise (Fig. 11.7.).
FIG. 11.7 β1 Receptor agonists.
Drugs that activate the β1 receptor are used in heart failure to improve the contractile state of the failing heart. They also increase heart rate, but excess stimulation can induce significant increases in heart rate and arrhythmias
11.4 β2-RECEPTOR ACTIVATING DRUGS β2 Receptors are found in bronchial smooth muscle and blood vessels of skeletal muscle, arterioles, heart, lung, uterus, and liver. Therapeutic applications of β2 activation are limited to the lungs and the uterus. Because drugs that activate β2
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receptors cause smooth muscle relaxation in the lung promoting bronchodilation and help relieve or prevent asthma attacks, β2 agonists are used for treatment of airways dysfunction such as bronchial asthma, chronic bronchitis, and emphysema, and in cases of premature labor for relaxing uterine smooth muscle. Drugs used for their β2-activating ability also can be classified as shortacting— albuterol (11.4.1), pirbuterol (11.4.2), procaterol (11.4.3), orciprenaline (11.4.5), terbutaline (11.4.6), fenoterol (11.4.7), and isoprenaline (11.4.8)—and long-acting— formoterol (11.4.9), bambuterol (11.4.10), clenbuterol (11.4.11), and salmeterol (11.4.12)—drugs (Fig. 11.8.).
FIG. 11.8 β2 Receptor agonists.
Most side effects of β2 agonists result from their concurrent β1 activity and include an increase in heart rate, a rise in systolic pressure, a decrease in diastolic pressure, chest pain, and arrhythmia.
11.5 DOPAMINE-RECEPTOR ACTIVATING DRUGS Dopamine receptors are involved in many neurological functions, such as motivation, memory, motor control, endocrine signaling. Dysfunction of dopaminergic neurotransmission in the CNS could be a reason of some neuropsychiatric disorders. There are at least five subtypes of dopamine receptors, D1 to D5. Some dopamine agonists can treat the hypodopaminergic state of organism, which is viewed as one of the main causes that triggers drug-seeking and taking; they are typically used for relieving Parkinson disease symptoms and restless legs syndrome.
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Activation of peripheral dopamine receptors causes dilation of the renal vasculature. This effect is exploited in the treatment of shock: by dilating renal blood vessels, renal perfusion is improved, thereby reducing the risk of renal failure. Dopamine itself is a drug that can activate dopamine receptors. It should be noted that, when dopamine is given to treat shock, the drug also enhances cardiac performance (because it activates β1 receptors in the heart). Common dopamine receptor agonists are dopamine (11.3) itself, apomorphine (11.5.1), bromocriptine (11.5.2), cabergoline (11.5.3), lisuride (11.5.4), pergolide (11.5.5), pramipexole (11.5.6), ropinirole (11.5.7), rotigotine (11.5.8), ciladopa (11.5.9), and derivatives of hexidine, namely, dihydrexidine (11.5.10), dinapsoline (11.5.11), and dinoxyline (11.5.12) (Fig. 11.9.).
FIG. 11.9 Dopamine receptor agonists.
11.6 MULTIPLE ADRENORECEPTOR ACTIVATION Anaphylactic shock is a manifestation of severe allergy. The reaction is characterized by hypotension (from widespread vasodilation), bronchoconstriction, and edema of the glottis. Epinephrine (11.1), is the treatment of choice for anaphylactic shock. Benefits derive from activating three types of adrenergic receptors: α1, β1, and β2. By activating these receptors, epinephrine can reverse the most-severe manifestations of the anaphylactic reaction. Activation of β1 receptors increases cardiac output, thereby helping elevate blood pressure. Blood pressure is also increased because epinephrine promotes α1-mediated vasoconstriction. In addition to increasing blood pressure, vasoconstriction helps
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suppress glottal edema. By activating β2 receptors, epinephrine can counteract bronchoconstriction. Mixed-acting drugs are epinephrine (11.1), norepinephrine (11.2), dobutamine (11.5), ephedrine (11.14), pseudoephedrine (11.1.1), and amphetamine (11.8). Synthesis of the most of the discussed drugs is described in our previous book [3].
11.7 DOPAMINE-RECEPTOR AGONIST BESTSELLER DRUGS On the list of Top 200 Drugs by sales for the 2010s are Guanfacine–Intuniv (11.2.5) and Albuterol (Salbutamol)–Ventolin (11.4.1)
Guanfacine–Intuniv Guanfacine is a classic, centrally acting antihypertensive known to stimulate central α2-adrenoceptors, which induces peripheral sympathoinhibition and hence reduces elevated blood pressure, predominantly as a result of vasodilation and a consequent decrease in peripheral vascular resistance. Its antihypertensive efficacy is beyond doubt, but the profile of adverse reactions is considered unfavorable [4,5]. Possible adverse reactions include blurred vision, confusion, dizziness, sweating, unusual tiredness, and weakness. Nevertheless guanfacine is one of the bestselling drugs for reducing high blood pressure. Moreover, after the discovery that the prefrontal cortex, which regulates behavior, thought, and emotion, is among the most evolved brain regions and that many cognitive disorders involve impairment of the prefrontal cortex [6], guanfacine was found to be capable of managing attention deficit hyperactivity disorder [7,8]. The synthesis of guanfacine is pretty simple and consists of an interaction of 2,6-dichlorophenylacetyl chloride or ethyl 2,6-dichlorophenyl acetate (11.7.1) with guanidine [9]. An alternate synthesis proposed by the same authors includes formylation of 2,6-dichlorophenylbenzyl cyanide (11.7.2) with ethyl formate to prepare a formylphenylacetonitrile derivative (11.7.3), which, after condensation with guanidine, produced (11.7.4), which was hydrated using hydrochloric acid to produce the desired guanfacine (11.2.5) [10,11] (Scheme 11.1.).
SCHEME 11.1 Synthesis of guanfacine.
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Albuterol–Salbutamol Albuterol is a short-acting β2-adrenergic receptor agonist and for more than 25 years was used to relieve bronchospasms in conditions such as asthma, bronchospasm, and other obstructive pulmonary diseases. Its side effects include restlessness, irritability, nervousness, sometimes tremor, and increased or irregular heart rate [12-14]. The two general methods for the synthesis of albuterol are based on two starting materials: substituted benzophenones and salicylic acid derivatives. The general approach started from 4-hydroxyacetophenone is described as follows [15] (Scheme 11.2.): 4-Hydroxyacetophenone (11.7.5) Blanc chloromethylation using formaldehyde and hydrogen chloride produces 4-hydroxy-3-chloromethylyacetophenone (11.7.6), which was acylated with a mixture of acetic anhydride, acetic acid, and sodium acetate to yield ketone (11.7.7). Bromination of the obtained ketone produces bromoketone (11.7.8), which on reaction with N-benzyl-N-t-butyl amine produces the aminoketone (11.7.9). After hydrolysis of acetyl groups with hydrochloric acid, the keto group in the diol (11.7.10) was reduced with sodium borohydride to give the triol (11.7.11). The triol was debenzylated with hydrogen using a Pd-C catalyst to produce the desired albuterol (11.4.1). Different modifications of this general approach have been proposed [16-22].
SCHEME 11.2 Synthesis of albuterol.
An approach started from methyl salicylate is outlined in Scheme 11.3 [16,17]. Methyl salicylate (11.7.12) was acylated with bromoacetyl chloride and the obtained bromoketone (11.7.13), on reaction with N-benzyl-N-t-butyl amine, produced aminoketone (11.7.14). Hydrogenation of the aminoketone with lithium aluminium hydride produced the known triol (11.7.11), which on debenzylation with hydrogen by Pd-C catalyst produced the desired albuterol (11.4.1).
SCHEME 11.3 Synthesis of albuterol.
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The details for both methods are discussed in the review [18]. The two enantiomers of the drugs are usually found to have significantly different potencies, but in the case of albuterol, effects of (R)-albuterol compared with (R,S)-albuterol, which have been documented in various cells and in vivo animal models, remain controversial [19-22].
REFERENCES 1. Brunton, L.; Lazo, J. S.; Parker, K.; Goodman, L. S.; Gilman, A. G. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, 2006. 2. Lemke, T. L.; David, A.; Williams, D. A. Foye’s Principles of Medicinal Chemistry, 6th ed.; Lippincott Williams & Wilkins, 2008. 3. Vardanyan, R. S.; Hruby, V. J. Synthesis of Essential Drugs; Elsevier, 2006. 4. Scholtysik, G.; Jerie, P.; Picard, C. W. Guanfacine. In Pharmacology of Antihypertension Drugs; Scriabine, A., Ed.; Raven Press, 1980; pp 79–98. 5. Scholtysik, G.; Fetkovska, N. Pharmacology of guanfacine. Cor Vasa 1987, 29 (4 Suppl. 1), S11–S16. 6. Arnsten, A. F. T.; Jin, L. E. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J. Biol. Med. 2012, 85 (1), 45–58. 7. Posey, D. J.; McDougle, C. J. Guanfacine and guanfacine extended release: treatment for ADHD and related disorders. CNS Drug Rev. 2007, 13 (4), 465–474. 8. Bukstein, O. G.; Head, J. Guanfacine ER for the treatment of adolescent attention-deficit/ hyperactivity disorder. Expert Opin. Pharmacother. 2012, 13 (15), 2207–2213. 9. Bream, J. B.; Picard, C. W. Acetylguanidine derivatives, FR 1584670 (1969). 10. Bream, J. B.; Picard, C. W. Phenylacetylguanidines, CH511816 (1971). 11. Bream, J. B.; Lauener, H.; Picard, C. W.; Scholtysik, G.; White, T. G. Substituted phenylacetylguanidines, a new class of antihypertensive agents. Arzneim. Forsch. 1975, 25 (10), 1477–1482. 12. Ahrens, R. C.; Smith, G. D. Albuterol: an adrenergic agent for use in the treatment of asthma. Pharmacology, pharmacokinetics and clinical use, Pharmacotherapy 1984, 4 (3), 105–121. 13. Price, A. H.; Clissold, S. P. Salbutamol in the 1980s. A reappraisal of its clinical efficacy, Drugs 1989, 38 (1), 77–122. 14. Colice, G. L. Albuterol HFA for the management of obstructive airway disease. Expert Rev. Respir. Med. 2008, 2 (2), 149–159. 15. Lunts, L. H. C.; Toon, P. Hydroxy-αγ-(aminomethyl)-m-xylene-α’,α3-diols as stimulators, US 3644353 (1972). 16. Lunts, L. H. C.; Toon, P. 1-Phenyl-2-aminoethanol derivatives as bronchodilators, US 3705233 (1972). 17. Collin, D. T.; Hartley, D.; Jack, D.; Lunts, L. H. C.; Press, J. C.; Ritchie, A. C.; Toon, P. Saligenin analogs of sympathomimetic catechol amines. J. Med. Chem. 1970, 13 (4), 674–680. 18. Skachilova, S. Y.; Zueva, E. F.; Muravskaya, I. D.; Goncharenko, L. V.; Smirnov, L. D. Procedures for preparing salbutamol (a review). Khim.-Farm. Zh. 1991, 25 (10), 59–65. 19. Hartley, D.; Middlemiss, D. Absolute configuration of the optical isomers of salbutamol. J. Med. Chem. 1971, 14 (9), 895–896.
Adrenergic (Sympathomimetic) Drugs Chapter | 11 199 20. Hawkins, C. J.; Klease, G. T. Relative potency of (-)- and (plus-)-salbutamol on guinea pig tracheal tissue. J. Med. Chem. 1973, 16 (7), 856–857. 21. Bakale, R. P. The development of routes to (R)-albuterol hydrochloride. Spec. Chem. 1995, 15 (6), 249–250. 253. 22. Barnes, P. J. Treatment with (R)- albuterol has no advantage over racemic albuterol. Rebuttal by Dr. Barnes, Am. J. Respir. Crit. Care Med. 2006, 174 (9), 974.