Medicinal Chemistry of Sympathomimetic Drugs

MEDICINAL CHEMISTRY OF SYMPATHOMIMETIC DRUGS

Phenylethylamine may be considered the parent compound from which sympathomimetic drugs are derived (Figure 9–4). This compound consists of a benzene ring with an ethylamine side chain. Substitutions may be made on (1) the benzene ring, (2) the terminal amino group, and (3) the α orβ carbons of the ethylamino chain. Substitution by –OH groups at the 3 and 4 positions yields sympathomimetic drugs collectively known as catecholamines. The effects of modification of phenylethylamine are to change the affinity of the drugs for α and β receptors, spanning the range from almost pure α activity (methoxamine) to almost pure β activity (isoproterenol), as well as to influence the intrinsic ability to activate the receptors.

In addition to determining relative affinity to receptor subtype, chemical structure also determines the pharmacokinetic properties and bioavailability of these molecules.

A.Substitution on the Benzene Ring

Maximal α and β activity is found with catecholamines, ie, drugs having –OH groups at the 3 and 4 positions on the benzene ring. The absence of one or the other of these groups, particularly the hydroxyl at C₃, without other substitutions on the ring may dra-matically reduce the potency of the drug. For example, phe-nylephrine (Figure 9–5) is much less potent than epinephrine; indeed, α-receptor affinity is decreased about 100-fold and β activity is almost negligible except at very high concentrations. On the other hand, catecholamines are subject to inactivation by catechol- O-methyltransferase (COMT), and because this enzyme is found in the gut and liver, catecholamines are not active orally . Absence of one or both –OH groups on the phe-nyl ring increases the bioavailability after oral administration and prolongs the duration of action. Furthermore, absence of ring –OH groups tends to increase the distribution of the molecule to the central nervous system. For example, ephedrine and amphet-amine (Figure 9–5) are orally active, have a prolonged duration of action, and produce central nervous system effects not typically observed with the catecholamines.

B. Substitution on the Amino Group

Increasing the size of alkyl substituents on the amino group tends to increase β-receptor activity. For example, methyl substitution on norepinephrine, yielding epinephrine, enhances activity at β₂ receptors. Beta activity is further enhanced with isopropyl substi-tution at the amino group (isoproterenol). Beta₂-selective agonists generally require a large amino substituent group. The larger the substituent on the amino group, the lower the activity at α recep-tors; for example, isoproterenol is very weak at α receptors.

C. Substitution on the Alpha Carbon

Substitutions at the α carbon block oxidation by monoamine oxi-dase (MAO) and prolong the action of such drugs, particularly the noncatecholamines. 

Ephedrine and amphetamine are examples of α-substituted compounds (Figure 9–5). Alpha-methyl com-pounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylam-ines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves . Therefore, a portion of their activity is dependent on the presence of normal norepinephrine stores in the body; they are indirectly acting sympathomimetics.

D. Substitution on the Beta Carbon

Direct-acting agonists typically have a β-hydroxyl group, although dopamine does not. In addition to facilitating activation of adre-noceptors, this hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles.