1. HMU/College of Pharmacy Dept. Pharmaceutical Chemistry
ADRENERGIC AGENTS 1
Dr. Dana Ameen
HMU/College of Pharmacy
Dept. Pharmaceutical Chemistry
22nd October 2017

2. Catecholamines
The name catecholamine 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.

3. Stability of catecholamines
Catecholamines undergo oxidation in the presence of oxygen (air) or other oxidizing agents to produce ortho-quinone-like compounds, which undergo further reactions to give mixtures of colored products. Hence, solutions of catecholamine drugs often are stabilized by the addition of an antioxidant (reducing agent) such as ascorbic acid or sodium bisulfite.

4. The active enantiomer
Epinephrine and NE each possess a chiral carbon atom; thus, each can exist as an enantiomeric pair of isomers. The enantiomer with the (R) configuration is biosynthesized in the body and possesses the biological activity.

5. Catecholamines are hydrophilic
As they are polar substances that contain acidic (the aromatic hydroxyls pKa 8.7) and basic (the aliphatic amine pKa 9.9).

6. Catecholamines Biosynthesis

7. Metabolism of catecholamine

8. α- and β-Adrenergic Receptors
The α1 and α2 receptors each have been divided into at least three subtypes: αlA, α1B, α1D and α2A, α2B, α2C, respectively.
The β1-receptors exhibit the agonist potency order isoproterenol > epinephrine = NE
While β2-receptors exhibit the agonist potency order isoproterenol > epinephrine >> NE.
The β3-receptor, the agonist potency order is isoproterenol = NE > epinephrine.

9. Drugs Affecting Catecholamine Biosynthesis
Metyrosine (α-methyl-p-tyrosine) is inhibiting tyrosine hydroxylase.
It is the (—) isomer that possesses the inhibitory activity but the racemic mixture is used.
Metyrosine is used orally for the preoperative management of pheochromocytoma.
Mainly excreted unchanged in the urine and because of its limited water solubility, crystalurea is a potential serious side effect.

10. Drugs Affecting Catecholamine Storage
Reserpine, deserpidine and rescinnamine Reserpine is an indole alkaloid obtained from the root of Rauwolfia serpentina, a climbing shrub found in India.
Reserpine binds with the ATP-driven monoamine transporter that transports NE and other biogenic amines from the cytoplasm into the storage vesicle.
Both the pure alkaloid and the powdered whole root of R. serpentina are used in the treatment of hypertension.

11. Reserpine is extensively metabolized through hydrolysis of the ester function at position 18. This yields methyl reserpate and 3,4,5-trimethoxybenzoic acid.
As is typical of many indole alkaloids, reserpine is susceptible to decomposition by light and oxidation.

12. Drugs Affecting Catecholamine Release
Guanethidine and Guanadrel prevent the release of NE from sympathetic nerve terminals and are used clinically in the treatment of hypertension.
The presence of the very basic guanidino group (pKa> 12) means that at physiological pH they are essentially completely protonated. Thus, these agents do not get into the CNS.

13. Guanethidine
Guanadrel
Bioavailability
3-50%
85%
Half-life
5 days
12 hours
Both agents are partially metabolized (~50%) by the liver, and both are used to treat moderate-to-severe hypertension.

14. Bretylium Tosylate
It is an aromatic quaternary ammonium compound used as an antiarrhythmic drug.
Its antiarrhythmic actions are not due to its neuronal blocking effects.

15. SYMPATHOMIMETIC AGENTS
Direct-acting agents elicit a sympathomimetic response by interacting directly with adrenergic receptors.
Indirect-acting agents produce effects primarily by causing the release of NE from adrenergic nerve terminals: the NE that is released by the indirect-acting agent activates the receptors to produce the response.
Mixed-acting agents interact directly with adrenergic receptors and cause the release of NE.

16. Direct-Acting Sympathomimetics STRUCTURE-ACTIVITY RELATIONSHIPS
Maximal activity is seen in β-phenylethylamine derivatives containing hydroxyl groups in the meta and para positions of the aromatic ring (a catechol) and a β-hydroxyl group of the correct stereochemical configuration on the ethylamine portion of the molecule. Such as NE, epinephrine, and isoproterenol.

17. Easson-Stedman hypothesis interaction of three critical pharmacophoric groups of (-)-(R)-NE with the complementary areas on the adrenergic receptor

18. The amino group
The amino group should be separated from the aromatic ring by two carbon atoms for optimal activity.
Primary and secondary amines are potent direct-acting agonists
Tertiary or quaternary amines are poor direct agonists.
1o and 2o

19. The amino group
As the bulk of the nitrogen substituent increases, α-receptor agonist decreases and β-receptor activity increases.
Example: Isoproterenol has little affinity for α-receptors but it is a potent β1 and β2-receptor agonist.

20. The nature of the substituent can also affect β1/β2-receptor selectivity.
Example, N-tert-butyl norepinephrine is 10 times as potent an agonist at tracheal β2-receptors than at cardiac β1-receptors.
Large substituents on the amino group also protect the amino group from undergoing oxidative deamination by MAO.

21. Substitution on the α-carbon
Alkyl substitution on the α-carbon reduces direct receptor agonist activity at both α- and β- receptors.
But an α-alkyl group increases the duration of action of the phenylethylamine agonist by making the compound resistant to metabolic deamination by MAO. Such compounds often exhibit enhanced oral effectiveness and greater CNS activity than their counterparts that do not contain an α-alkyl group.

22. Substitution on the α-carbon
α-Methyl substitution gives compounds with selectivity toward the α2-recepor.
α-Ethyl substitution results in compounds with selectivity toward the β2-receptor
Another effect of α-substitution is the introduction of a chiral center. Example, with α-methylnorepinephrine, it is (1R,2S)-isomer that possesses significant activity at α-receptors.

23. Replacement of the catechol moiety
Replacement of the catechol function of isoproterenol with the resorcinol structure gives the drug metaproterenol, which is a selective β2-agonist. The resorcinol ring is not a substrate for COMT, has better absorption characteristics and a longer duration of action.

24. Replacement of the catechol moiety
Replacement of the meta-hydroxyl of the catechol structure with a hydroxymethyl group gives agents, such as albuterol, which show selectivity to the β2-receptor. As in the case of the resorcinol modification, they are not metabolized by COMT and thus show improved oral bioavailability.

25. Replacement of the catechol moiety
Removal of the p-hydroxyl group from epinephrine gives phenylephrine, which, in contrast to epinephrine, is selective for the α1-adrenergic receptor.

26. Imidazoline α-adrenergic receptor agonists
These imidazolines can be nonselective, or they can be selective for either the α1- or α2-adrenergic receptors. Structurally, imidazolines for the most part have the heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via some type of bridging unit.

27. Imidazoline α-adrenergic receptor agonists
Modification of the imidazoline ring generally results in compounds with significantly reduced agonist activity, there are examples of so-called open-ring imidazolines (guanabenz and guanfacine) that are highly active.

28. Imidazoline α-adrenergic receptor agonists
The optimum bridging unit (X) is usually a single amino or methylene group.

29. Imidazoline α-adrenergic receptor agonists
The nature of the aromatic moiety, as well as how it is substituted, is quite flexible.
However, agonist activity is enhanced when the aromatic ring is substituted with halogen substituents like Cl or small alkyl groups like methyl, particularly when they are placed in the two ortho-positions.

30. ENDOGENOUS CATECHOLAMINES
The three naturally occurring catecholamines dopamine, norepinephrine (NE), and epinephrine are used as therapeutic agents.

31. Dopamine
Dopamine is used in the treatment of shock. It is used intravenously as it is ineffective orally, in large part because it is a substrate for both MAO and COMT.

32. Norepinephrine (NE)
Like the other endogenous catecholamines, it is a substrate for both MAO and COMT and thus is not effective by the oral route of administration.
The enantiomer with the (R) configuration is biosynthesized in the body and possesses the biological activity.

33. Epinephrine
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 indicates oxidative breakdown.

34. Epinephrine
To minimize oxidation, solutions of the drug are stabilized by the addition of reducing agents such as sodium bisulfite. As the free amine, it is used in aqueous solution for inhalation.
Like other amines, it forms salts with acids; for example, those now used include the hydrochloride and the bitartrate.

35. Epinephrine
It is destroyed readily in alkaline solutions and by metals (Cu, Fe, Zn), weak oxidizing agents, and oxygen of the air.
It is not effective by the oral route because of poor absorption and rapid metabolism by MAO and COMT.
The irritation often experienced on instillation of epinephrine into the eye has led to its development of other preparations of the drug that potentially are not as irritating. One such example is dipivefrin.

36. Dipivefrin (dipivalyl epinephrine)
Dipivefrin is a prodrug of epinephrine that 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 much better penetration of the eye when administered topically as an aqueous solution for the treatment of primary open-angle glaucoma.

37. Dipivefrin is converted to epinephrine by esterases in the cornea and anterior chamber. It 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 concentration than epinephrine.

38. α-ADRENERGIC RECEPTOR AGONISTS
Phenylephrine is the prototypical selective direct-acting α1-receptor agonist.
It is active when given orally, and its duration of action is about twice that of epinephrine. It is metabolized by MAO, but since it lacks the catechol moiety, it is not metabolized by COMT.

39. Methoxamine
It is selective direct-acting α1-receptor agonist used therapeutically.
It is less potent than phenylephrine as a vasoconstrictor. Methoxamine is used primarily during surgery to maintain adequate arterial blood pressure, especially in conjunction with spinal anesthesia. It does not stimulate the CNS.

40. Midodrine
Midodrine represents another example of a dimethoxy-β-phenylethylamine derivative that is used therapeutically for its vasoconstrictor properties.
Midodrine is the N-glycyl prodrug of the selective α­1-receptor agonist desglymidodrine. Removal of the N-glycyl moiety from midodrine occurs readily in the liver as well as throughout the body, presumably by amidases.

41. Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline
The 2-aralkylimidazolines are agonists at both α1 and α2-adrenergic receptors. These agents are used for their vasoconstrictive effects as nasal and ophthalmic decongestants.

42. Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline
They have limited access to the CNS, since they essentially exist in an ionized at physiological pH because of the very basic nature of the imidazoline ring (pKa 9 to 10).

43. Clonidine
It is an example of α-(phenylimino)imidazolidine derivative that possesses selectivity for the α2-adrenergic receptor.
The ability of clonidine and its analogues to exert an antihypertensive effect depends on the ability of these compounds not only to interact with the α2-receptor but also to gain entry into the CNS.

44. SAR of clonidine and its analogues
In the case of clonidine, the basicity of the guanidine group (typically pKa 13.6) is decreased to 8.0 (the pKa of clonidine) because of its direct attachment to the dichlorophenyl ring. Thus, at physiological pH, clonidine will exist to a significant extent in the nonionized form required for passage into the CNS.

45. SAR of clonidine and its analogues
Substitutions on the aromatic ring with various halogen and alkyl can be placed at the two ortho positions without affecting the affinity of the derivatives toward α2-receptors, such substitutions have a marked effect on the lipophilicity of the compound to gain entry into the CNS to produce an antihypertensive effect.

46. SAR of clonidine and its analogues
Halogen substituents such as chlorine seem to provide the optimal characteristics in this regard. This distributive phenomenon is seen with one of the metabolites of clonidine, 4-hydroxyclonidine. This compound has good affinity for α2-receptors, but since it is too polar to get into the CNS, it is not an effective antihypertensive agent.

47. Guanabenz and Guanfacine
Structurally, these analogues of clonidine can be considered "open-ring imidazolidines". In these compounds, the 2,6-dichlorophenyl moiety found in clonidine is connected to a guanidino group by a two-atom bridge.
In the case of guanabenz, this bridge is a —CH=N— group, while for guanfacine it is a —CH2CO—moiety. For both compounds, conjugation of the guanidino moiety with the bridging moiety helps to decrease the pKa of this normally very basic group so that at physiological pH a significant portion of each drug exists in its nonionized form.

48. Guanabenz and Guanfacine
Clonidine
Guanfacine
Guanabenz
Elimination half-life (hours)
20-25 17 6
Excreted unchanged in the urine (%) 60 50
Very little

49. Apraclonidine and Brimonidine
Both are selective α2-receptor agonists with α1:α2 of 30:1 and 1000:1, respectively.
Tizanidine finds use in treating spasticity associated with multiple sclerosis or spinal cord injury. By stimulating α2-adrenergic receptors, it is believed to decrease the release of excitatory amino acid neurotransmitters from spinal cord inter-neurons.

50. Methyldopa
The presence of an α-methyl group in the correct configuration on the phenylethylamine nucleus yields compounds with increased potency at α2-receptors and decreased potency at α1-receptors.
Although α-methylnorepinephrine is not given as a drug, it is the metabolic product of the drug methyldopa.
It is postulated that α-methylnorepinephrine acts on α2-receptors in the CNS in the same manner as clonidine, to decrease sympathetic outflow and lower blood pressure.

52. Methyldopa
Methyldopa is used only by oral administration since its zwitterionic character limits its solubility.
Absorption can range from 8-62% and appears to involve an amino acid transporter. Absorption is affected by food, and about 40% of that absorbed is converted to methyldopa-O-sulfate by the mucosal intestinal cells.
Entry into the CNS also appears to involve an active transport process.

53. Methyldopate (Aldomet ester)
The ester hydrochloride salt of methyldopa, was developed as a highly water-soluble derivative that could be used to make parenteral preparations.

54. DUAL α- AND β-ADRENERGIC RECEPTOR AGONISTS
Dobutamine: can be viewed as an analogue of dopamine in which a 1-(methyl)-3-(4-hydroxyphenyl)propyl substituent has been placed on the amino group. This substitution gives a compound that possesses an asymmetric carbon atom. Thus, dobutamine exists as a pair of enantiomers, with each enantiomer possessing a distinct pharmacology.

55. Dobutamine
The (+) enantiomer is a potent full agonist at both and β1 and β2 receptors.
In contrast, the (—) enantiomer is some 10 times less potent at β1 and β2 receptors. The (—) enantiomer is, however, a potent agonist at α1 receptors.

56. Racemic mixture of dobutamine
Inotropic and chronotropic effects of the heart, is the result of a combination of the inotropic effect of (+)-one on β1-receptors and that of (—)-one mediated through α1-receptors. Thus, a racemic mixture provides a more desirable pharmacological and therapeutic effect than would either enantiomer alone.

57. Pharmacokinetics of dobutamine
It is given by intravenous infusion, since it is not effective orally.
Solutions of the drug can exhibit a slight pink color as a result of oxidation of the catechol function.
It has a plasma half-life of about 2 minutes, It is metabolized by COMT and conjugation but not by MAO.

58. β-ADRENERGIC RECEPTOR AGONISTS
Isoproterenol is the prototypical β-adrenergic (both β1, and β2) receptor agonist. Because of an isopropyl substitution on the nitrogen atom, it has virtually no effect on α receptors.
Isoproterenol is available for use by inhalation and injection.

59. Pharmacokinetics of isoproterenol
After oral administration, the absorption of isoproterenol is rather erratic and undependable. The drug has a duration of action of 1-3 hours after inhalation.
The principal reason for its poor absorption characteristics and relatively short duration of action is its facile metabolic transformation by sulfate and glucuronide conjugation of the ring hydroxyls and methylation by COMT.
Unlike epinephrine and NE, isoproterenol does not appear to undergo oxidative deamination by MAO. Since it is a catechol, it is sensitive to light and air. Aqueous solutions become pink on standing.

60. Metaproterenol and Terbutaline
Modification of the catechol portion of a β agonist has resulted in the development of selective β2-receptor agonists.
They are resorcinol derivatives that are β2 selective. They are much more effective when given orally, and they have a longer duration of action. This is because they are not metabolized by either COMT or MAO. Instead, their metabolism primarily involves glucuronide conjugation.

61. Albuterol, Pirbuterol, and Salmeterol
They are examples of selective β2-receptor agonists whose selectivity results from replacement of the meta-hydroxyl group of the catechol ring with a methyl 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 COMT or MAO, instead, they are conjugated with sulfate. They thus are active orally, and they exhibit a longer duration of action than isoproterenol. The duration of action of terbutaline, albuterol, and pirbuterol is in the range of 3-6 hours.

62. Salmeterol It is very long acting (12 hours), an effect attributed to:
The lipophilic phenylalkyl substituent on the nitrogen atom, which is believed to interact with a site outside but adjacent to the active site.
This agent associates with the β2-receptor slowly and dissociates from the receptor at an even slower rate.

63. Formoterol and Levalbuterol.
Formoterol has a long duration of action which results from its association with the membrane lipid bilayer.
The (R) isomer of the phenylethanolamines possesses the pharmacological activity and the inactive (S) isomer may be responsible for some of the adverse effects.
Levalbuterol: the (R) isomer of racemic albuterol.

64. Isoetharine Isoetharine Isoproterenol
Weaker at stimulating β2-receptors
Stronger
Not metabolized by MAO
metabolized
Duration of action similar

65. Bitolterol → Colterol
Bitolterol is a prodrug of the selective β2-adrenergic agonist colterol, the N-tert-butyl analogue of NE.
Bitolterol →
Colterol
More lipophilic
Inhalation
Longer duration (5-8 hour)
Hydrolysis by esterases
Metabolized by COMT and Conjugation

66. Ritodrine
Ritodrine is a selective β2-receptor agonist used to control premature labor and to reverse fetal distress caused by excessive uterine activity.
Usually, it is administered initially by intravenous infusion to stop premature labor. Subsequently, it may be given orally.

67. β3-Adrenergic Receptor Agonists
They have been developed, but they have not been approved for therapeutic use.
Stimulation of the β3-receptor promotes lipolysis.
So, may have antiobesity and for the treatment of NIDD non-insulin-dependent diabetes.