Structureactivity Relationships

The structure-activity relationships (SARs) summary is shown in Figure 16.11. Comprehensive reviews of the SARs of a- and [-agonists and antagonists33-35 covered their developments in the late 1980s. The parent structure with the features in common for many of the adrenergic drugs is [-phenylethylamine. The manner in which [-phenylethylamine is substituted on the meta- and para-positions of the aromatic ring, on the amino (R1), and on a-, (R2)-, and [-positions of the ethylamine side chain influences not only their mechanism of action, the receptor selectivity, but also their absorption, oral activity, metabolism, degradation, and thus duration of action (DOA). For the direct-acting sympathomimetic amines, maximal activity is seen in [-phenylethylamine derivatives containing (a) a catechol and (b) a (1^)-OH group on the ethylamine portion of the molecule. Such structural features are seen in the prototypical direct-acting compounds NE, E, and ISO. The SARs are supported by the model of [2-AR binding studies (Fig. 16.8).

Optical Isomerism. A critical factor in the interaction of adrenergic agonists with their receptors is stereoselectivity. Substitution on either carbon-1 or carbon-2 yields optical isomers. (1^,2s) isomers seem correct configuration for direct-acting activity. For CAs, the more potent enan-tiomer has the (1R) configuration. This enantiomer is typically several 100-fold more potent than the enantiomer with the (1S) configuration. It appears that for all direct-acting, phenylethylamine-derived agonists that are structurally similar to NE, the more potent enantiomer is capable of assuming a conformation that results in the arrangement in space of the catechol group, the amino group, and the (1r)-OH group in a fashion resembling that of (1r)-NE. This explanation of stereoselectivity is based on the presumed interaction of these three critical pharmacophoric groups with three complementary binding areas on the receptor and is known as the Easson-Stedman hypothesis.17,36 This three-point interaction is supported by site-directed mutagenesis studies28 on the adrenergic receptor and is illustrated in Figure 16.8.

Aromatic substituents

3', 4'-diOH for both a & p agonist activity metabolized by COMT->

poor oral activity and short DOA hydrophilic -» poor CNS activity

3', 5'-diOH (e.g., metaproterenol) 3'-CH2OH, 4'-OH (e.g., albuterol) T p2 activity

T absorption, oral activity, & DOA

4'-OH is more important for (3 activity 3'-OH is more important for a activity (e.g., phenylephrine: a-agonist)

No phenolic substitution: 4both a and p activity direct or indirect activity

Structure required for activity:

^ 1. p-Phenylethylamine 2. Catechol ring 3 (1 R)-OH

^ 1. p-Phenylethylamine 2. Catechol ring 3 (1 R)-OH

R2-Sustitution on C2 small alkyl groups (Me, Et) tolerated i degration by MAO

still substrates for COMT -» little effect on DOA Et group:

I a » p (more p-selective, e.g., ethylnorepinephrine) T CNS activity T oral activity & DOA (2S) methyl group: T a2 activity

R-i-Substitution on N

T the size of R-|-> T p activity I a activity t-butyl: T p2 activity 4- degradation by MAO

R2-Sustitution on C2 small alkyl groups (Me, Et) tolerated i degration by MAO

still substrates for COMT -» little effect on DOA Et group:

I a » p (more p-selective, e.g., ethylnorepinephrine) T CNS activity T oral activity & DOA (2S) methyl group: T a2 activity

Figure 16.11 • Structure-activity relationship of adrenergic phenylethylamine agonists.

Separation of Aromatic Ring and Amino Group.

By far, the greatest adrenergic activity occurs when two carbon atoms separate the aromatic ring from the amino group. This rule applies with few exceptions to all types of activities.

R1, Substitution on the Amino Nitrogen Determines a- or Receptor Selectivity. 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 also dramatically affects the receptor selectivity of the compound. As the size of the nitrogen substituent increases, a-receptor agonist activity generally decreases and j-receptor agonist activity increases. Thus, NE has more a-activity than j-activity and E is a potent agonist at a-, jj i-, and j2-receptors. ISO, however, is a potent ji- and j2-agonist but has little affinity for a-receptors.

The nature of the substituents can also affect j1- and j2-receptor selectivity. In several instances, it has been shown that a jS2-directing N-tert-butyl group enhances jS2-selectivity. For example, N-tert-butylnorepinephrine (Colterol) is 9 to 10 times more potent as an agonist at tracheal jS2-receptors than at cardiac ^-receptors. These results indicate that the jS-re-ceptor has a larger lipophilic binding pocket adjacent to the amine-binding aspartic acid residue than do the a-receptors. Increasing the length of the alkyl chain offers no advantage, but if a polar functional group is placed at the end of the alkyl group, the situation changes. In particular, adding a phenol group to the end of a C2 alkyl chain results in a dramatic rise in activity, indicating that an extra polar-binding region has been accessed, which can take part in H-bonding. Experiments have shown the activity of the extension analog is thereby increased by a factor of 800. As R1 becomes larger than butyl group, it can provide compounds with ^-blocking activity (e.g., tamsulosin and labetalol). Large substituents on the amino group also protect the amino group from undergoing oxidative deamination by MAO.

R2, Substitution on the a-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. The 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 lipophilic-ity, such compounds often exhibit enhanced oral effectiveness and greater CNS activity than their counterparts that do not contain an a-alkyl group. In addition, compounds with an a-methyl substituent persist in the nerve terminals and are more likely to release NE from storage sites. For example, metaraminol is an a-agonist and also exhibits a greater degree of indirect sympathomimetic activity.

Methyl or ethyl substitution on the a-carbon of the eth-ylamine side chain reduces direct agonist activity at both a- and jS-receptors. a-Substitution also significantly affects receptor selectivity. An ethyl group in this position diminishes a-activity far more than jS-activity, affording compounds with jS-selectivity (e.g., ethylnorepinephrine and isoetharine). In the case of jS-receptors, for example, a-methyl or ethyl substitution results in compounds toward the jS 2-selectivity, whereas in the case of a-receptors, a-methyl substitution gives compounds toward the a2-selectivity. Another effect of a-substitution is the introduction of a chiral center, which has pronounced effects on the stereochemical requirements for activity. For example, with a-methylnorepinephrine, it is the erythro (1R,2S) isomer that possesses significant activity at a2-receptors.

OH substitution on the fi-carbon (carbon-1) generally decreases CNS activity largely because it lowers lipid solubility. However, such substitution greatly enhances agonist activity at both a- and jS-receptors. For example, ephedrine is less potent than methamphetamine as a central stimulant, but it is more powerful in dilating bronchioles and increasing blood pressure and heart rate. Compounds lacking the jS-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. The R-enantiomer of NE is more active than the S-enantiomer, indicating that the secondary alcohol is involved in an H-bonding interaction.

Substitution on the Aromatic Ring. Maximal a- and jS-activity also depends on the presence of 3' and 4' OH groups. Tyramine, which lacks two OH groups, has no affinity for adrenoceptors, indicating the importance of the OH groups. Studies of S-adrenoceptor structure suggest that the OH groups on serine residues 204 and 207 probably form H-bonds with the catechol OH groups at positions 3' and 4', respectively.

Pharmacophore Thylamine

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 adren-ergic agonists. This approach has been used in particular in the design of selective ¡2-agonists. For example, replacement of the catechol function of ISO with the resorcinol structure gives a selective ¡2-agonist, metaproterenol. Furthermore, because the resorcinol ring is not a substrate for COMT, ¡-agonists that contain this ring structure tend to have better absorption characteristics and a longer DOA than their catechol-containing counterparts. In another approach, replacement of the meta-OH of the catechol structure with a hydroxymethyl group gives agents, such as albuterol, which show selectivity to the ¡2-receptor. Because they are not catechols, these agents are not metabolized by COMT and thus show improved oral bioavailability and longer DOA.

Modification of the catechol ring can also bring about selectivity at a-receptors as it appears that the catechol moiety is more important for a2-activity than for ai-activity. For example, removal of the p-OH group from E gives phenylephrine, which, in contrast to E, is selective for the ai-receptor. Phenylephrine is less potent than E at both a-and ¡-receptors, with ¡2-activity almost completely absent. However, the OH group can be replaced by other groups capable of interacting with the binding site by H-bonding. This is particularly true for the meta-OH group, which can be replaced by CH2OH, NHMe, NHCOR, NMe2, or NHSO2R group.

CAs without OH Groups. Phenylethylamines that lack OH groups on the ring and the ¡-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. Because substitution of OH groups on the phenylethylamine structure makes the resultant compounds less lipophilic, unsubstituted or alkyl-substituted compounds cross the BBB more readily and have more central activity. Thus, amphetamine and metham-phetamine exhibit considerable CNS activity.

CAs per oral have only a brief DOA and are almost inactive, because they are rapidly inactivated in the intestinal mucosa and in the liver before reaching the systemic circulation. In contrast, compounds without one or both phenolic OH substituents are, however, not metabolized by COMT, and they are orally active and have longer DOA.

Imidazolines and a-Adrenergic Agonists. Although nearly all ¡-agonists are ¡-phenylethanolamine derivatives, it is a-adrenoceptors that exhibit a far more diverse assortment of structures. A second chemical class of a-agonists, the

X = usually CH2 (a-i agonists) or NH (a2 agonists)

Figure 16.12 • General structural features of the imidazoline «-adrenergic receptor agonists.

X = usually CH2 (a-i agonists) or NH (a2 agonists)

Figure 16.12 • General structural features of the imidazoline «-adrenergic receptor agonists.

imidazolines, which give rise to a-agonists and are thus vasoconstrictors. These imidazolines can be nonselective, or they can be selective for either ai- or a2-receptors. Structurally, most imidazolines have their heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via some type of bridging unit (Fig. 16.12).34 The optimum bridging unit (X) is usually a single methylene group or amino group. Although modification of the imidazoline ring generally results in compounds with significantly reduced agonist activity, there are examples of so-called open-ring imidazolines that are highly active. 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 chlorine (Cl) or small alkyl groups like methyl group, particularly when they are placed in the two ortho positions. Because the SARs of the imidazolines are quite different from those of the ¡-phenylethylamines, it has been postulated that the imidazolines interact with a-recep-tors differently from the way the ¡-phenylethylamines do, particularly with regard to the aromatic moiety.37

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Responses

  • Kasey
    Why albutetol not metabolized by COMT?
    9 months ago

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