Chapter 13 Review Question Answers
1. An electronegative group (e.g., Cl, CF3, or SCH3) is required at the 2-position of
the phenothiazine ring for antipsychotic activity. A three-carbon bridge separating
the N-10 nitrogen of the phenothiazine ring and the side chain amine is necessary.
The basic side chain nitrogen can be a tertiary amine (dimethylamino) or part of a
heterocyclic ring (e.g., piperidine or piperazine). Shortening the chain to two
carbons leads to a loss of antipsychotic activity and may impart antihistaminic
activity.
2. In rotigotine and ropinirole, there is 2-C separation from the aromatic ring and the
basic side chain amine. This corresponds to the 2-C separation between the
phenyl ring and the side chain amino group in dopamine. A catechol nucleus is
not required for activation of D3 receptors. The 5-hydroxy group on the tetralin
nucleus of rotigotine corresponds to the meta-OH of dopamine. In ropinirole, the
lactam moiety that is part of the 2-indolone nucleus is considered bioisosteric with
the meta-OH of dopamine. The side chain tertiary amine in both rotigotine and
ropinirole imparts increased D3 activity and inhibits both compounds from direct
oxidative deamination by MAO.
3.
4. Coadministration of the AADC inhibitor carbidopa with levodopa is necessary to
prevent peripheral decarboxylation of levodopa to dopamine. This allows the dose
of levodopa to be decreased, resulting in fewer side effects (e.g., nausea and
vomiting). Addition of the COMT inhibitor entacapone to the levodopa/carbidopa
combination prevents inactivation of levodopa to 3-O-methyldopa (3OMD). This
metabolite may block uptake of levodopa into the brain.
Ch. 13 Review Question Answers
1
5. Both clozapine and olanzapine act as antagonists at the D2 and 5HT2A receptors.
Inhibitory 5HT neurons terminate on presynaptic DA neurons in the striatum.
Antagonism of presynaptic 5HT2A receptors leads to an increase in DA release.
This increase is thought to attenuate D2 blockade caused by antipsychotics. The
decreased EPS caused by atypical antipsychotics has been suggested to be due to
5HT2A receptor blockade. The phenyl ring in clozapine and the 2-methylthiophene
moiety in olanzapine are considered bioisosteres.
Ch. 13 Review Question Answers
2