Optional reading assignment: Wilson and Gisvold, pgs. 656-673
Adrenergic agents (also known as sympathomimetics) are drugs that mimic or block the action of norepinephrine and epinephrine at postganglionic synapses of the sympathetic nervous system, and in the CNS. The endogenous neurotransmitters norepinephrine and epinephrine are neurotransmitters at the postganglionic synapses of smooth muscle and glands in the vasculature, the gut and the bronchii. Norepinephrine synthesis occurs in sympathetic nerve terminals, where it is stored in granules until it is released by depolarization of the neural membrane. Epinephrine synthesis occurs primarily in the adrenal medulla, and is secreted into the general circulation and transported to adrenergic receptor sites.
Endogenous Adrenergic NeurotransmittersThe existence of two subtypes of adrenoreceptors was first proposed by Ahlquist in 1948. According to his theory, the two types, which he termed ß a and b, had different functions at their respective sites of action. Eventually, two primary types of b receptor (b1 and b2) were elucidated. It was later found that heart tissue contained a 4:1 ratio of b1:b2 receptors, while the ratio of b2 to b1 receptors in the bronchii was 3:1. By contrast, a-receptors are primarily located on vasculature smooth muscle. Later, a1 and a2 receptor subtypes were also identified. As we will see, this has great significance in the design of synthetic adrenergic agents, and allows compounds with somewhat similar structures to be used for different therapeutic purposes. A diagram of the pre- and postsynaptic b receptor appears below. Notice that norepinephrine can stimulate both pre- and postsynaptic receptors, that it can be taken up into the presynaptic neuron by uptake 1, and that it can be taken up into the postsynaptic neuron by uptake 2.
Adrenergic agonists can be classified by their action on adrenergic receptors. Direct agonists are compounds that bind to the receptor and cause a response through their intrinsic activity. Indirect adrenergic agonists bind to the receptor, and produce an effect by releasing epinephrine or norepinephrine. They may also inhibit the reuptake of norepinephrine in the synapse. Finally, some agents have mixed action, in that they have partial agonist characteristics, but also release epi or norepi. The pharmacophore for adrenergic agents is shown below. The aromatic ring is numbered as indicated, with the sidechain being attached at C-1. On the ethylamino sidechain, carbons are designated a and b, with respect to the amino group. Changes in the structure of the pharmacophore can cause alterations in a/b specificity, activity, distribution, and so on.
The endogenous neurotransmitters (also called catecholamines) contain three required structural features. They contain a catechol nucleus (i.e. hydroxyl groups in the meta and para position on the aromatic ring), a b-hydroxy group and a nitrogen substituent. The R-(-)-configuration (of the b-hydroxyl group) is most active enantiomer. As we will see below, it is the N-substituent that determines whether the activity of the compound is a or b.When R = H, the compound is norepinephrine, and when it is a methyl, the compound is epinephrine. Catechols are notoriously unstable, and catecholamines are no exception. In the presence of air and light, they oxidize to form quinones, which have no adrenergic activity. For this reason, solutions of catecholamines are kept at alkaline pH in sealed, brown glass containers.
The biosynthetic pathway leading to the endogenous catecholamines is shown below. The amino acid tyrosine is transported into the nerve terminal, where it is hydroxylated to form L-DOPA by tyrosine hydroxylase. This enzyme is the rate limiting step in the biosynthesis of epi and norepi. L-DOPA is next decarboxylated to form dopamine - this requires the enzyme DOPA decarboxylase. The b-hydroxyl group is stereospecifically added by dopamine-b-hydroxylase, forming norepinephrine. This enzyme also hydroxylates the b position of other phenethylamines. In the adrenal medulla, phenylethanolamine-N-methyltransferase utilizes S-adenosylmethionine to add an N-methyl group to form epinephrine.
After they are released, catecholamines must be removed from the synapse to allow repolarization of the neural membrane. This is accomplished largely by reuptake of these neurotransmitters into the presynaptic nerve terminal. There are also 2 enzymes which metabolize catecholamines, as well as a number of synthetic adrenergic agents. The enzyme catechol-O-methyltransferase (COMT), another SAM-dependent enzyme, places a methyl group on the meta hydroxyl of the catechol nucleus. This forms an inactive derivative. COMT absolutely requires a catechol nucleus in its substrate, and only adds a methyl to the meta OH. Monoamine oxidase (MAO) reacts with any phenethylamine that contains two a-hydrogens. This oxidative deamination forms the corresponding aldehyde, which can be reduced by aldehyde reductase to form the alcohol, or can spontaneously oxidize to form the carboxylate. Because MAO and COMT can both act on a single catecholamine molecule, the major urinary metabolite of epi and norepi is vanallylmandelic acid (VMA), shown below.
Return to the PHA 4110 Homepage