Lec.: fifteen Pharm.

chemistry

‫بقلم زميلي الدكتور فاضل محسن الحسيني‬

‫جامعة ذي قار‬/‫استاذ الكيمياء الصيدالنية في كلية الصيدلة‬

‫بتصرف‬

DRUGS AFFECTING ADRENERGIC NEUROTRANSMISSION

Drugs Affecting Catecholamine Biosynthesis

1. Metyrosine (α-Methyl-L-tyrosin):
a. metyrosine is a much more effective competitive inhibitor of Ep and NE production
than agents that inhibit any of the other enzymes involved in CA biosynthesis.
b. it differs structurally from tyrosine only in the presence of an α-methyl group and
used principally for the preoperative management of pheochromocytoma.

Home work: Inhibitors of CA synthesis have limited clinical utility. Why ?.

2- α-methyl-m-tyrosine:

a. It is used in the treatment of shock.

 b. It differs structurally from metyrosine only in the presence of m-OH instead of p-OH
in metyrosine. This unnatural amino acid is accepted by the enzymes of the
biosynthetic pathway and converted to metaraminol (an α-agonist).

3-Inhibitors of AADC (e.g., carbidopa): these agents are used to inhibit the metabolism of
drug L-DOPA administered in the treatment of Parkinson disease

Drugs Affecting Catecholamine Storage and Release:

1. Reserpine:
a. It is an indole alkaloid obtained from the root of Rauwolfia serpentina found in
India.
b. reserpine is susceptible to decomposition by light and oxidation.
c. It not only depletes the vesicle storage of NE in sympathetic neurons in PNS,
neurons of the CNS, and Ep in the adrenal medulla, but also depletes the
storage of serotonin and DA in their respective neurons in the brain.
d. Reserpine binds extremely tightly with and blocks VMAT that transports NE
and other biogenic amines from the cytoplasm into the storage vesicles. Thus,
NE, will be metabolized by mitochondrial MAO in the cytoplasm.
Home work: When reserpine is given orally, its maximum effect is seen after a couple of
weeks. A sustained effect up to several weeks is seen after the last dose has been
given……..why?,

2. Guanethidine and guanadrel:

a. they are seldom used orally as active antihypertensives Drugs.
b. They act by entering the adrenergic neuron by way of the uptake-1 process and
accumulate within the neuronal storage vesicles where they bind to the storage
vesicles and stabilize the neuronal storage vesicle membranes, making them less
responsive to nerve impulses. The ability of the vesicles to fuse with the neuronal
membrane is also diminished, resulting in inhibition of NE release into the
synaptic cleft.
Sympathomimetic agents:

1. These agents produce effects resembling those produced by stimulation of the

sympathetic nervous system.
2. They may be classified according to their mechanism of action as agents that produce
effects by:
a. Direct acting: elicit a sympathomimetic response by interacting directly with
adrenergic receptors
b. Indirect acting: produce effects primarily by causing the release of NE from
adrenergic nerve terminals
c. Mixed acting: interact directly with adrenergic receptors and indirectly cause the
release of NE.

Direct-Acting Sympathomimetics Structure-activity relationship (SAR)

1. The parent structure with the features in common for many of the adrenergic drugs
is β-phenylethylamine.
2. The manner in which β-phenylethylamine is substituted on the meta- and para-
positions of the aromatic ring + on the amino group (R1), and on α-carbon (R2)-, and
β-positions of the ethylamine side chain influences their:
a. mechanism of action.
b. the receptor selectivity.
c. absorption, oral activity.
d. metabolism, degradation and thus duration of action (DOA).
3. For the direct-acting sympathomimetic amines, maximal activity is seen in β-
phenylethylamine derivatives containing:
a. Catecholic two hydroxyl groups on the aromatic ring.
 b. (1R) is OH group on the α-carbon of the ethylamine portion of the molecule.
Such structural features are seen in the prototypical direct-acting compounds NE,
Ep, and ISO.

4. Separation of Aromatic Ring and Amino Group by far than two carbones
tremendously reduces CAs agonistic activity. The greatest adrenergic agonsitic
activity occurs when two carbon atoms separate the aromatic ring from the amino
group.
5. Optical Isomerism: is a critical factor in the interaction of adrenergic agonists with
their receptors is stereoselectivity. Where any substitution on either carbon-1 or
carbon-2 yields optical isomers.
Note:
 (1R,2S) isomers seem correct configuration for direct-acting activity.

Home work: For CAs, the more potent enantiomer has the (1R) configuration ……..Why?

6. Substitution on the Amino group Nitrogen:

 The amine is normally ionized at physiological pH. This is important for direct
agonist activity, because replacing nitrogen with carbon results in a large decline in
activity.
 The activity is also affected by the number of substituents on the nitrogen. Primary
and secondary amines have good adrenergic activity, whereas tertiary amines and
quaternary ammonium salts do not.
 The nature of the amino substituent dramatically affects the receptor selectivity
(α/β adrenoceptors selectivities) of the compound: As the size of the nitrogen
 substituent increases, α-receptor agonist activity generally decreases and β-
receptor agonist activity increases.
Examples:
 NE has more α-activity than β-activity.
 Ep is a potent agonist at α-, β1-, and β2-receptors.
 ISO, however, is a potent β1- and β2-agonist but has little affinity for α-
receptors……………….explain why (through chemical structures).
 The nature of the substituents can also affect β1/β2-receptors selectivity: In
several instances, it has been shown that N-tert-butyl group substitiution enhances
β2-selectivity (have β2-selectivity directing effect).
Example:
 N-tert-butylnorepinephrine (Colterol) is 9 to 10 times more potent as 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.

7. Substitution on the α-Carbon (Carbon-2):

 Substitution by small alkyl group (e.g., CH3- or C2H5-) slows metabolism by MAO but
has little overall effect on DOA of catechols because they remain substrates for
COMT. However, the resistance to MAO activity is more important in noncatechol
indirect-acting phenylethylamines. Therefore; DOA of drugs such as ephedrine or
amphetamine is thus measured in hours rather than in minutes. Because addition of
small alkyl group increases the resistance to metabolism and lipophilicity.
 compounds with an α-methyl substituent persist in the nerve terminals and are more
likely to release NE from storage sites.
Example:
 metaraminol is an α-agonist and also exhibits a greater degree of indirect
sympathomimetic activity
 Methyl or ethyl substitution on the α-carbon of the ethylamine side chain reduces
direct agonist activity at both α- and β-receptors.
 Another effect of α-substitution is the introduction of a chiral center, which has
pronounced effects on the stereochemical requirements for activity.
Example:
 α-methylnorepinephrine (the erythro 1R, 2S) isomer possesses significant
activity at α2-receptors.

 OH substitution on the β-carbon (carbon-1): in general it largely decreases

CNS activity because it lowers lipid solubility. However, such substitution
greatly enhances agonist activity at both α- and β-receptors.

Notes:
i. Compounds lacking the β-OH group (e.g. DA) have a greatly reduced
adrenergic receptor activity. Some of the activity is retained, indicating
that the OH group is important but not essential for aderenergic activity.
ii. The R-enantiomer of NE is more active than the S-enantiomer, indicating
that the secondary alcohol is involved in an H-bonding interaction
8. Substitution on the Aromatic Ring: Maximum α- and β-receptors activity is also
depends on the presence of the caticholic 3′ and 4′ OH groups. Tyramine, which lacks
two OH groups, has no affinity for adrenoceptors, indicating the importance of the
OH groups.
 Although the catechol moiety is an important structural feature in terms of
yielding compounds with maximal agonist activity at adrenoceptors, it can be
replaced with other substituted phenyl moieties to provide selective
 adrenergic agonists. This approach has been used in particular in the design of
selective β2-agonists.
Example:
 replacement of the catechol function of ISO with the resorcinol
structure gives a selective β2-agonist, metaproterenol. Furthermore,
because the resorcinol ring is not a substrate for COMT, β-agonists that
contain this ring structure tend to have better absorption
characteristics and a longer DOA than their catechol-containing
counterparts.

 Modification of the catechol ring can also bring about selectivity at α-receptors
where the catechol moiety is more important for α2-activity than for α1-activity.
Example:
 removal of the p-OH group from E gives phenylephrine, which, in contrast to
Ep, is selective for the α1-receptor.
9. CAs without OH Groups like Phenylethylamines that lack OH groups on the ring and
the β-OH group on the side chain act almost exclusively by causing the release of NE
from sympathetic nerve terminals and thus results in a loss of direct
sympathomimetic activity.

Phenylephrine
 Imidazolines and α-Adrenergic Agonistsic activity

1. Although nearly all β-agonists are β-phenylethanolamine derivatives a second

chemical class of α-agonists ( the imidazolines) have been developed.
2. Structurally, most imidazolines have a heterocyclic imidazoline nucleus linked to a
substituted aromatic moiety via some type of bridging unit (the optimum bridging
unit is usually a single methylene group or amino group).
3. Imidazoline derivatives give rise to α-agonists and are thus vasoconstrictors.
4. These imidazolines can be nonselective, or they can be selective for either α1- or α2-
receptors.