Chapter 11 Case Study Answer
Conduct a thorough and mechanistic SAR analysis of the 3 therapeutic options in the case.
5-HT3 antagonists share a common structural motif: an aromatic ring, a hydrogen-accepting
carbonyl moiety coplanar with the aromatic ring, and a relatively unhindered basic nitrogen atom
all separated by a defined distance. The 1-azabicyclo[2.2.2]octane (quinuclidine) ring system of
compound 1 is reminiscent of the tropane ring system (8-azabicyclo[3.2.1]octane) of cocaine, the
drug that served as the template for the development of selective 5-HT3 antagonists. These two
ring systems are known to provide high potency 5-HT3 antagonism. The restrained bicyclic ring
ensures a sterically unrestricted amino nitrogen which is presumed to bind to the 5-HT3 receptor
(a ligand-gated ion channel) in protonated form. The nature of the aromatic ring can vary, and
substitution, when present, is generally limited to lipophilic and/or small groups.
5-HT3 antagonists have found a therapeutic niche in the prevention of cancer chemotherapy
and/or radiation-induced nausea and vomiting (CINV). In addition to being a highly selective 5HT3 antagonist, compound 1 also binds persistently to its receptor. Some authors have estimated
its affinity for 5-HT3 receptors as over 30 times that of “1st generation” antagonists without a
concomitant increase in side effects (Aapro, Ther Clin Risk Manag 2007;3(6):1009-1020).
With an elimination half-life of up to almost 2 days, compound 1 is retained in vivo for
an extended period. It produces a prolonged therapeutic effect that is useful in treating both the
acute and the delayed phases of CINV. It is slowly metabolized to two clinically inactive
metabolites, the N-oxide and the 6-hydroxy analog. The hydroxylation reaction is stereospecific.
CYP2D6 catalyzes the bulk of the biotransformation, but 2D6 phenotype does not impact the
activity or side effect profile of this drug and the risk of drug-drug interaction is low. While some
clinically significant cardiac toxicity has been observed with 5-HT3 antagonists, compound 1 is
not among them. The increase in QTc interval produced by this agent has been deemed clinically
insignificant and it is considered safe to use in patients with underlying cardiovascular disease.
Compound 2 is another 5-HT3 antagonist that has replaced the azabicyclic ring system
found in compound 1 with imidazole. These two ring systems are the most common and potent
carriers for the required basic amino nitrogen atom. The aromatic ring is now indole and the Haccepting group is a ketone. These two groups are coplanar, as required, and the single sp2
hybridized atom separation of the carbonyl and benzo component of the indole ring is optimal.
The indole and imidazole rings of compound 2 are substituted with small, lipophilic methyl
groups, which honors steric restriction rules for these areas of the antagonist. While these
differences in structure do not alter selectivity for the 5-HT3 receptor, compound 2 does not bind
with the tenacity of compound 1.
Compound 2 is vulnerable to inactivating metabolism, with CYP3A4 catalyzing the
predominant indole hydroxylation reaction. Indole hydroxylation also occurs at C7 and both
monophenols and the catechol are found in the serum of patients on this antiemetic. The 4 hour
elimination half-life of this agent is the shortest of all of the drugs in its class. The lower binding
affinity and more facile metabolic inactivation of compound 2 result in a much shorter duration
of therapeutic action in the prevention of CINV compared to 1. Compound 2 is also known to
prolong the QTc interval. In addition, while not anticipated based on mechanism or metabolic
profile, compound 2 may decrease the effectiveness of cisplatin, requiring higher doses of this
highly toxic chemotherapeutic agent. The physiologic reason for this drug-drug interaction is
currently unknown.
Compound 3 is an indolealkylamine or tryptamine that, while having high affinity for the
5-HT1D receptor, also binds to other receptors within the 5-HT1 family, including 5-HT1B
(originally classified as a 5-HT1D receptor subtype) and, to a lesser extent, 5-HT1A. It has no
affinity for 5-HT2 or 5-HT3 receptors. Compound 3 acts as an agonist at 5-HT1D and 5-HT1B sites
in the trigeminal nerve and meningeal arteries, respectively. Stimulation of these receptors leads
to vasoconstriction that brings relief to migraine headache sufferers. This action is not selective
for the CNS however, and the ability of 5-HT1B/1D agonists to constrict peripheral arterial vessels
through their stimulation of 5-HT1D receptors in vascular smooth muscle means they are
contraindicated in patients with hypertension and/or coronary artery disease. Compound 3 and its
active secondary amine metabolite have a relatively short half-life of 3 hours.
Apply the chemical understanding gained from the SAR analysis to this patient’s specific
needs to make a therapeutic recommendation.
Sr. MT is in need of a long-acting 5-HT3 receptor antagonist to guard against the acute
and delayed emetogenic action of both drugs that will be included in her chemotherapy regimen.
Compound 1 (palonosetron) would be an ideal agent to assist her in managing this highly
distressful response to cisplatin and doxorubicin. Given IV 30 minutes prior to chemotherapy,
palonosetron has been shown to control acute chemotherapy-associated nausea and vomiting, as
well as the delayed CINV that can occur up to 5 days after drug administration. Days 2-3 are
notoriously the worst for delayed CINV, and palonosetron shows a significantly greater
antiemetic activity during this time period than other 5-HT3 antagonists. The impact of this drug
on cardiovascular function is negligible, so it should not pose toxicity problems given Sr. MT’s
underlying hypertension and hyperlipidemia.
Compound 2 (ondansetron) would have a protective effect against acute CINV similar to
palonosetron, but it does not have a duration of action sufficiently long to adequately manage the
delayed nausea and vomiting that this patient will undoubtedly face. In addition, while not
always observed in the clinic, it could potentially diminish the efficacy of the cisplatin,
necessitating an increase in dose that could increase Sr. MT’s risk of cisplatin-induced
ototoxicity and nephrotoxicity. Ondansetron would be very useful in some chemotherapy
regimens, but not optimally beneficial in this one.
Compound 3 (zolmitriptan) is the wrong drug to select for several reasons. First and
foremost, it has no affinity for the 5-HT3 receptor and, therefore, cannot antagonize it to bring
about the desired antiemetic effect. It does bind to 5-HT1 receptors, but acts as an agonist rather
than an antagonist. While stimulating central 5-HT1A receptors could conceivably bring about
some anxiolytic effects, the impact would be minimal since the affinity of zolmitriptan for this
subtype is low. Finally, zolmitriptan’s predominant action in the periphery (5-HT1D receptor
stimulation in vascular smooth muscle) would cause Sr. MT’s normally high blood pressure to
rise to potentially dangerous levels.
Victoria F. Roche, Ph.D. and S. William Zito, Ph.D.