Ans: Unlike norepinephrine or epinephrine, Neo-synephrine lacks the catechol moiety therefore it is not a substrate for COMT. Thus, it should have longer duration of action than NE or epinephrine.

b. How many stereoisomers can you write for a-methyl NE? Which isomer is the active isomer at the a₂-adrenergic receptors?

Ans: a-Methyl NE has two chiral centers. Thus, it should have four stereoisomers, i.e., (1R, 2R), (1R, 2S), (1S, 2R), and (1S, 2S). The active isomer at the a₂-adrenergic receptors is the (1R, 2S) a-methylnorepinephrine.

c. With your knowledge of how drugs are metabolized by the cytochrome P-450 enzymes, explain why methoxamine and M-7 possess adrenergic agonist activities.

Ans: Metoxamine may require O-demethylation of the m-metoxy group before it will bind to the a₁-receptors while M-7 needs to be N-demethylated to give a secondary amine which is required at the adrenergic receptors (i.e., a tertiary amine is inactive at the adrenergic receptors).