Structure Activity Relationships Among Adrenomimetic Drugs

The nature of the substitutions made on the basic phenylethylamine skeleton at the para and meta positions of the benzene ring or on the p-carbon of the side chain determine whether an adrenomimetic drug will act directly or indirectly. Directly acting adrenomimetic drugs, which have two or more carbon atoms (e.g., isopro-terenol) added to their amino group, are virtually pure p-adrenoceptor agonists. Directly acting drugs, which have only small substitutions on their amino groups (e.g., nor-epinephrine and epinephrine), are usually «-adrenoceptor agonists, but may be p-adrenoceptor agonists as well. Norepinephrine has very weak actions on p2-adrenocep-tors but strong p1-adrenoceptor actions. Epinephrine has a high affinity for both p1- and p2-adrenoceptors.

Adrenomimetic drugs with no substitutions on their benzene ring (e.g., amphetamine and ephedrine) are generally quite lipid soluble, readily cross the blood-brain barrier, and can cause central nervous system (CNS) stimulation.

The structure of a particular adrenomimetic drug will influence its susceptibility to metabolism by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The actions of COMT are specific for the cate-chol structure. If either the meta or para hydroxyl group is absent, COMT will not metabolize the drug. The presence of a substitution, such as a methyl group, on the acarbon of the side chain reduces the affinity of the adrenomimetic drug for MAO. Also, drugs with a large substitution on the terminal nitrogen will not be degraded by MAO. A noncatecholamine that has a methyl group attached to its a-carbon will not be metabolized by either enzyme and will have a greatly prolonged duration of action (e.g., amphetamine).

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