Medicinal Chemistry

4.3.5.5 Drugs Acting on Presynaptic Adrenergic Receptors

As mentioned in section 4.3.3, there are two kinds of αreceptor in brain and peripheral
tissues. The crucial experiments have shown that brain tissue prelabeled with [^3 H]NE
will release neurotransmitter upon electrical stimulation or exposure to K+. The release is
reduced by the αagonist clonidine (4.42) and stimulated by the αantagonist yohimbine
(4.43). Since the adrenoreceptor involved in this latter experiment plays a vital role in mod-
ulating neurotransmitter release, it must be presynaptic and located on the nerve-ending
membrane. A similar selectivity has also been shown by peripheral tissues (heart, uterus),
leading to the distinction of α 1 (postsynaptic) and α 2 (presynaptic) adrenergic receptors.
There are also presynaptic βreceptors,which show a feedback regulation opposite to that
of the α 2 receptors; that is, their excitation by a neurotransmitter increases NE release.

Epinephrine and norepinephrine show the same affinity for both α 1 andα 2 receptors as
do some antagonists such as phentolamine (4.44). Sometimes receptor selectivity depends
upon the drug concentration: dihydroergocryptine (4.45), a partial α-blocking agent, binds
at a low concentration to α 1 receptors; at higher concentrations, however,α 2 binding takes
over, at the point where the Scatchard plot indicates a positive cooperativity of sites. This
concentration dependence is logical, considering the NE-release stimulation at a high dose
of the blocking agent but not at a low dose, where the blocking action is not severe.
Other imidazolines related to clonidine, like naphazoline (4.46), are also α 2 agonists.
In general,α-methyl substituents on phenethylamines increase their α 2 affinity, as does
loss of the 3–OH group. Loss of the 4–OH group of the catechol nucleus promotes α 1
activity.

4.3.6 Adrenergic Drugs: Postsynaptic Effects

Adrenergic drugs may also exert postsynaptic effects. There is a considerable body of
classical structure–activity correlation studies in the adrenergic field for these effects. It
may be summarized as follows:

1. Phenolic hydroxyls are important for adrenergic agonist activity. Removal of the
   4–OH group leaves intact only α-agonist activity, whereas removal of the 3–OH
   group abolishes bothα- and β-agonist activity. The 3–OH group can, however,
   be replaced by a sulfonamide (soterenol) or a hydroxymethyl (salbutamol) group.
   3-Amino compounds can be extremely potent. Replacement of the 4–OH group by

228 MEDICINAL CHEMISTRY