1. Medicinal Chemistry II / lecture 4 3rd stage/ 2nd semester 28/3/2019
ADRENERGIC AGENTS
Medicinal Chemistry II / lecture 4
3rd stage/ 2nd semester
28/3/2019

2. ENDOGENOUS CATECHOLAMINES
The three naturally occurring catecholamines DA, NE, and E are used as therapeutic agents.
Dopamine. (DA, 3,4-dihydroxyphenylethylamine)
As a catechol and primary amine, DA is rapidly metabolized by COMT and MAO and has a short DOA with no oral activity.
It is used intravenously in treatment of shock.
In contrast with the NE and E, DA 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, Na+ excretion, and, in turn, urinary output.
The dilation of renal blood vessels produced by DA is the result of its agonist action on the D1-DA receptor.

3. In doses slightly higher than those required to increase renal blood flow, DA stimulates the β1-receptors of the heart to increase cardiac output.
Infusion at a rate greater than 10 μg/kg per minute results in stimulation of α1- receptors, leading to vasoconstriction and an increase in arterial blood pressure.
Β1 effect: 2-10 μg/kg/min
Alpha effect: > 10 μg/kg/min
Dopaminergic effect: μg/kg/min

4. Norepinephrine: Like DA, it is polar and rapidly metabolized by both COMT and MAO, resulting in poor oral bioavailability and short DOA (1 or 2 minutes even when given intravenously).
It is a stimulant of α1-, α2-, and β1-adrenoceptors (notice that lacking the N-methyl group results in lacking β2- and β3-activity).
It is used to counteract various hypotensive crises, because its α -activity raises blood pressure and as an adjunct treatment in cardiac arrest because its β -activity stimulates the heart.
It has limited clinical application caused by the nonselective nature of its activities.
Epinephrine (E, Adrenalin): Like NE, it lacks oral activity and has short DOA.
However, it is much more widely used clinically than NE.
E is a potent stimulant of all α1-, α2-, β1-, β2-, and β3- adrenoceptors, and thus it switches on all possible adrenergic receptors, leading to a whole range of desired and side effects.

5. Dipivefrin (Propine, Dipivalyl Epinephrine).
Dipivefrin is a prodrug of E that is formed by the esterification of the catechol OH groups of E with pivalic acid.
Most of the advantages of this prodrug over E stem from improved bioavailability.
The greatly increased lipophilicity allows much greater penetrability into the eye through the corneal epithelial and endothelial layer.
Increased DOA is also achieved because the drug is resistant to the metabolism by COMT.

6. α-Adrenergic Receptor Agonists
All selective α1-agonists have therapeutic activity as vasoconstrictors.
Structurally, they include:
(a) phenylethanolamines such as phenylephrine, metaraminol, and methoxamine
(b) 2-arylimidazolines such as xylometazoline, oxymetazoline, tetrahydrozoline, and naphazoline.

7. Phenylephrine. (a prototypical selective direct-acting α1-agonist)
differs from E only in lacking a p-OH group.
It is orally active, and its DOA is about twice that of E because it lacks the catechol moiety and thus is not metabolized by COMT. However, its oral bioavailability is less than 10% because of its hydrophilic properties (log P= -0.3)
Metabolism: intestinal 3-O-glucuronidation/ sulfation and metabolism by MAO.
It is used in the treatment of severe hypotension resulting from either shock or drug administration.
It also has widespread use as a nonprescription nasal decongestant in both oral and topical preparations.
In the eye, it is used to dilate the pupil and to treat open-angle glaucoma.
It is used in spinal anesthesia to prolong the anesthesia and to prevent a drop in blood pressure during the procedure.

8. Methoxamine (Vasoxyl) is another α1-agonist and parenteral vasopressor used therapeutically and so have few cardiac stimulatory properties.
It is bioactivated by O-demethylation to an active m-phenolic metabolite.
Methoxamine is used primarily during surgery to maintain adequate arterial blood pressure, especially in conjunction with spinal anesthesia.

9. Naphazoline, tetrahydrozoline, xylometazoline (Otrivin), and oxymetazoline: are 2-arylalkylimidazolines α1-agonists.
These agents are used for their vasoconstrictive effects as nasal decongestants.
They have limited access to the CNS, because they essentially exist in an ionized form at physiological pH caused by the very basic nature of the imidazoline ring.

10. Clonidine (Catapres): Clonidine is an example of a (phenylimino) imidazolidine derivative that possesses central α2-selectivity.
Under certain conditions, such as intravenous infusion, clonidine can briefly exhibit vasoconstrictive activity as a result of stimulation of peripheral α-receptors.
However, this hypertensive effect, if it occurs, is followed by a much longer-lasting hypotensive effect as a result of the ability of clonidine to enter into the CNS and stimulate α2-receptors located in the brain.

11. Methyldopa (L-α-methyldopa, Aldomet)
Differs structurally from L-DOPA only in the presence of α- methyl group.
Originally synthesized as an AADC inhibitor, methyldopa ultimately decreases the concentration of DA, NE, E, and serotonin in the CNS and periphery.
However, its mechanism of action is not caused by its inhibition of AADC but, rather, by its metabolism in the CNS to its active metabolite (α-methylnorepinephrine).
Methyldopa is transported actively into CNS via an aromatic amino acid transporter, where it is decarboxylated by AADC in the brain to (1R,2S)-α-methyldopamine.
This intermediate, in turn, is stereospecifically β-hydroxylated by DBH to give the (1R,2S)-α-methylnorepinephrine.
This active metabolite is a selective α2-agonist.

13. DUAL α- AND β-AGONISTS/ANTAGONISTS
Dobutamine (Dobutrex) is a positive inotropic agent administered intravenously for congestive heart failure.
It possesses a center of asymmetry, and both enantiomeric forms are present in the racemic mixture used clinically.
The (-) isomer of dobutamine is a potent α1-agonist, which is capable of causing marked pressor responses.
In contrast, (+)-dobutamine is a potent α1-antagonist.
Both isomers appear to be full agonists, but the (+) isomer is a more potent β1-agonist than the (-) isomer (approximately tenfold)

14. Dobutamine contains a catechol group and is orally inactive and thus is given by intravenous infusion.
It has a plasma half-life of about 2 minutes because it is metabolized by COMT and by conjugation, although not by MAO.

15. β-Adrenergic Receptor Agonists
Isoproterenol (Isuprel) is a nonselective and prototypical β-agonist (β2/β1 = 1).
After oral administration, the absorption of ISO is rather erratic and undependable.
The principal reason for its poor absorption characteristics and relatively short DOA is its facile metabolism by sulfate and glucuronide conjugation of the phenolic OH groups and o-methylation by COMT.
The drug has DOA of 1 to 3 hours after inhalation.

16. It does act on both β1- and β2-receptors.
It can produce an increase in cardiac output by stimulating cardiac β1-receptors and can bring about bronchodilation through stimulation of β2- receptors in the respiratory tract.
In fact, it is one of the most potent bronchodilators available and is available for use by inhalation and injection.

17. Metaproterenol and terbutaline
Belong to the structural class of resorcinol bronchodilators.
3,5-diOH groups confer β2-receptor selectivity on compounds with large amino substituents.
They relax the bronchial musculature in patients with asthma but cause less direct cardiac stimulation than do the nonselective β-agonists.
their metabolism primarily involves glucuronide conjugation.

18. Albuterol, pirbuterol, and salmeterol
are examples of selective β2- agonists whose selectivity results from replacement of the meta-OH group of the aromatic ring with a hydroxymethyl moiety.
As in the case of metaproterenol and terbutaline, these drugs are not metabolized by either COMT or MAO. Instead, they are conjugated with sulfate.
They are thus orally active, and exhibit a longer DOA than ISO.

19. Ritodrine (Yutopar) is a selective β2-agonist that was developed specifically for use as a uterine relaxant.

20. Indirect-Acting Sympathomimetics
Indirect-acting sympathomimetics act by releasing endogenous NE. They also enter the nerve ending by way of the active-uptake process and displace NE from its storage granules.
the indirect-acting drugs that are used therapeutically are not catechol derivatives and, in most cases, do not even contain an OH moiety.
amphetamine and p-tyramine are often cited as prototypical indirect-acting sympathomimetics.

21. Hydroxyamphetamine (Paredrine) is an effective, indirect-acting sympathomimetic drug. It differs from amphetamine in the presence of p-OH group and so it has little or no CNS-stimulating action.
It is used to dilate the pupil for diagnostic eye examinations and for surgical procedures on the eye.

22. Sympathomimetics with a Mixed Mechanism of Action
Those phenylethylamines considered to have a mixed mechanism of action usually have no hydroxyls on the aromatic ring but do have a β-hydroxyl group.
Ephedrine, The drug acts on both α- and β-receptors directly and indirectly causes release of NE.
It is the classic example of a sympathomimetic with a mixed mechanism of action.
The drug is not metabolized by either MAO or COMT and therefore has longer DOA.
Indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia.

23. ADRENERGIC RECEPTOR ANTAGONISTS (BLOCKERS)
α-Blockers: Because α-agonists cause vasoconstriction and raise blood pressure, α-blockers should be therapeutically used as antihypertensive agents.
NONSELECTIVE α-BLOCKERS:
Tolazoline and phentolamine
Tolazoline is available in an injectable form and is indicated for use in persistent pulmonary hypertension of the newborn when supportive measures are not successful.
Phentolamine is used to prevent or control hypertensive episodes that occur in patients with pheochromocytoma.

24. IRREVERSIBLE α-BLOCKER
Although dibenamine is the prototypical agent in this class, it is phenoxybenzamine that is used therapeutically today.
Phenoxybenzamine: an old but powerful α-blocker, is a haloalkylamine that blocks α1- and α2- receptors irreversibly.
Oral phenoxybenzamine is used for the preoperative management of patients with pheochromocytoma and in the chronic management of patients whose tumors are not amenable to surgery.

25. SELECTIVE α1-BLOCKERS
Prazosin, terazosin, and doxazosin: are quinazoline α1-blockers
Structurally, these agents consist of three components: the quinazoline ring, the piperazine ring, and the acyl moiety.
The 4-amino group on the quinazoline ring is very important for α1-receptor affinity.

26. Alfuzosin: is also a quinazoline α1-blocker but differs from terazosin in replacing the piperazine ring in terazosin with an open piperazine ring.
Alfuzosin is more selective for the subtype of α1A-receptor in the prostate gland than those in vascular tissue. Thus, it has been used extensively in treating BPH
Tamsulosin: a nonquinazoline benzensulfonamide, is the first in the class of subtype selective α1A blocker.

27. SELECTIVE α2-BLOCKERS Yohimbine & Mirtazapine: selective α2-blockers.
Yohimbine is an indole alkylamine alkaloid; its structure resembles that of reserpine.
Yohimbine increases heart rate and blood pressure as a result of its blockade of α2-receptors in the CNS.

28. β-Blockers STRUCTURE–ACTIVITY RELATIONSHIPS
β-Blockers are among the most widely employed antihypertensives and are also considered the first-line treatment for glaucoma.
Most of β-blockers are in the chemical class of aryloxypropanolamines.
The first β-blocker, dichloroisoproterenol (DCI), was reported in 1958.
Unfortunately, DCI is not a pure antagonist but a partial agonist.
The substantial direct sympathomimetic action of DCI precluded its development as a clinically useful drug.

29. Pronethalol was the next important β-blocker developed.
It was withdrawn from clinical testing because of reports that it caused thymic tumors in mice.
Within 2 years of this report, however, Black and Stephenson described the β-blocking actions of propranolol, a close structural relative of pronethalol.

30. Propranolol belongs to the group of β-blockers known as aryloxypropanolamines.
This term reflects the fact that an -OCH2- group has been incorporated into the molecule between the aromatic ring and the ethylamino side chain.
Because this structural feature is frequently found in β-blockers, the assumption is made that the -OCH2- group is responsible for the antagonistic properties of the molecules.
However, this is not true; in fact, the -OCH2- group is present in several compounds that are potent β-agonists.

31. This latter fact again leads to the conclusion that it is the nature of the aromatic ring and its substituents that is the primary determinant of β-antagonistic activity.
The aryl group also affects the absorption, excretion, and metabolism of the β-blockers.
Propranolol (log P = 3.10) is the most lipophilic drug among the available β-blockers, and thus it enters the CNS much better than the less lipophilic drug such as atenolol (log P = 0.10) or nadolol (log P =1.29).
The use of lipophilic β-blockers such as propranolol has been associated with more CNS side effects, such as dizziness, confusion, or depression.
These side effects can be avoided, however, with the use of hydrophilic drugs, such as atenolol or nadolol.

32. NONSELECTIVE β-BLOCKERS (FIRST GENERATION)
Propranolol (Inderal) is the prototypical and nonselective β-blocker.
It blocks the β1- and β2-receptors with equal affinity
Despite cardiovascular use, because of its high lipophilicity (log P = 3.10) and thus its ability to penetrate the CNS, propranolol has found use in treating anxiety and is under investigation for the treatment of a variety of other conditions, including schizophrenia, alcohol withdrawal syndrome, and aggressive behavior.
Other Nonselective β-Blockers. Several other clinically used nonselective β-blockers include nadolol, pindolol, penbutolol, carteolol, timolol, levobunolol, sotalol, and metipranolol
Structures of these compounds are shown in Figure (page 552).

34. β1-SELECTIVE BLOCKERS (SECOND GENERATION)
β1-blockers are drugs that have a greater affinity for the β1-receptors of the heart than for β2-receptors in other tissues.
Such cardioselective agents should provide two important therapeutic advantages:
The first advantage should be the lack of a blocking effect on the β2-receptors in the bronchi.
Theoretically, this would make β1-blockers safe for use in patients who have bronchitis or bronchial asthma.
The second advantage should be the absence of blockade of the vascular β2-receptors, which mediate vasodilation.
This would be expected to reduce or eliminate the increase in peripheral resistance that sometimes occurs after the administration of nonselective β-blockers.

35. The following β1-selective blockers are used therapeutically: acebutolol, atenolol, betaxolol, bisoprolol, esmolol and metoprolol.

36. β-BLOCKERS WITH α1-ANTAGONIST ACTIVITY (THIRD GENERATION)
Labetalol & Carvedilol.
Carvedilol is a β-blocker that has a unique pharmacological profile. Like labetalol, it is a β-blocker that possesses α1-blocking activity. Only the (S) enantiomer possesses the β-blocking activity, although both enantiomers are blockers of the α1-receptor.

37. END