gene was first described in the Pima Indians, a population with a high incidence of
obesity. In the human receptor, this substituted amino acid at position 64 lies at the
junction of the first transmembrane spanning domain and the first intracellular loop. A
large number of studies suggest associations between the Trp64Arg β 3 receptor variant
and an increased capacity to gain weight, resistance to weight loss, increased blood
pressure, and coronary heart disease.
The β receptor is highly stereospecific, preferentially binding only to certain
stereoisomers of drugs. The conformational preference is a phenyl/NH 3 transarrange-
ment, meaning that the agonist molecule is extended, with the m-OH and β-OH coinci-
dent on the same face of the molecule. The agonist molecule therefore has a polar and
a nonpolar side.
4.3.5 Adrenergic Drugs: Presynaptic and Synaptic EffectsPresynaptic adrenergic drug effects may be classified as follows:
- Drugs acting on catecholamine synthesis
- Drugs acting on catecholamine metabolism
- Drugs acting on catecholamine storage
- Drugs acting on catecholamine reuptake
- Drugs acting on presynaptic receptors
These classes afford a logical, mechanistic approach to adrenergic drugs and each class
will be discussed individually.
4.3.5.1 Drugs Interfering with Catecholamine Synthesis
These drugs include various enzyme inhibitors; mechanisms of enzyme inhibition are
discussed in chapter 8. However, some of these agents have other, nonenzymatic points
of attack. The most widely used of these compounds isα-methyldopa (4.36). Like
many methyl analogs of enzyme substrates, this drug is a competitive inhibitor of
DOPA decarboxylase, and was believed to decrease blood pressure by decreasing avail-
able NE through inhibition of its synthesis. Other findings, however, indicated that
α-methyldopa is metabolized to α-methyl-NE, which then stimulates the central presy-
naptic α 2 receptors, thus decreasing NE release. The analogous α-methyltyrosine
inhibits tyrosine hydroxylase, but is not used as a drug. (Other DOPA decarboxylase
inhibitors will be discussed in connection with dopamine.)
NEUROTRANSMITTERS AND THEIR RECEPTORS 225