4.4.3 Postsynaptic Dopaminergic Drug Effects4.4.3.1 Dopamine Agonists
Besides dopamine itself, several highly active DA agonists are known, all exhibiting
the extended β-phenethylamine structure corresponding to a trans conformation.
(−)-Apomorphine (4.84), known for its emetic (i.e., vomit inducing) effect, is both a
pre- and a postsynaptic DA agonist or partial agonist, depending on the system; both
hydroxyl groups are necessary for activity. Interestingly, apomorphine is now also
being evaluated as an oral agent for the treatment of erectile dysfunction. N-alkylation,
β-hydroxylation (of DA), and α-methyl substitution all reduce central DA activity but
increase interaction with the peripheral adenylate cyclase.
Extremely active compounds are found among 2-aminotetralines. 6,7-Dihydroxy-
2-aminotetraline (4.85, ADTN) and its N-(n-propyl) derivative are well-studied
2-aminotetraline derivatives. Nomifensine (4.83) is related to these aminotetralines
and is used as an antidepressant drug. The catechol analog of nomifensine (with two
hydroxyls on the 4-phenyl ring) is also a potent inhibitor of NE and DA uptake.
Theergot alkaloids and their derivatives are a rich source of catecholaminergic
drugs. Ergot (Claviceps purpurea) is a parasitic fungus found on grasses and cereals
(rye). The long black sclerotium (“ergot”) of the fungus is cultivated. Because the fungus
is more valuable than the cereal crop, fields are artificially infected and the mixture of
indole alkaloids is extracted from the ripe sclerotia. One of these indole peptide alka-
loids, ergocryptine (4.86), is an α-adrenergic antagonist; however, its dihydro derivative
(on the double bond of the pyridine ring) is a potent D2 agonist that is used as a
242 MEDICINAL CHEMISTRY