acetylcholine receptors, and even the voltage-gated sodium channel protein. Beyond
this, tricyclic molecules have been suggested as a treatment for prion-based dementias
such as Creutzfeldt–Jakob disease or the human variant “mad cow disease.” A review
of the patent literature also discloses suggestions that tricyclics may be useful in the
treatment of Alzheimer’s disease. Consequently, the tricyclic moiety is regarded as a
preferred platform—a chemical structure that can be successfully exploited to produce
a wide range of drugs for very diverse clinical indications.
Case 1.1. A 19-year old female attempted “suicide by tricyclics” by ingesting 13.2 g
of carbamazepine (an anticonvulsant drug). She then had multiple seizures and was
taken to an emergency room in coma (secondary to the interaction of the drug with
voltage-gated Na+channels). By 18 h post-overdose she was awake, but was experi-
encing writhing movements in her arms (possibly secondary to the drug interacting with
dopamine receptors). Between 20 and 40 h post-overdose she had no “bowel sounds”
(i.e., no gastrointestinal peristalsis, secondary to the drug interacting with acetylcholine
receptors in the bowel). With supportive care, she ultimately made an uneventful recov-
ery (see Weaver et al., 1988). This not uncommon case exemplifies the range of recep-
tors available for binding to a tricyclic drug molecule.
The clinically relevant relationship between tricyclic structure and bioactivity can be
assessed using quantum pharmacology calculations. It is possible to quantify the spa-
tial relationships (butterfly angles) between the planes defined by the “aromatic wings”
of the tricyclic molecules. A series of angular descriptors (figure 1.15) can be used as
measures of these spatial relationships; these descriptors can be accurately calculated,
using molecular orbital calculations. Anticonvulsant effects are mediated primarily
through the voltage-gated Na+channel; antipsychotic effects are mediated primarily
through dopamine receptors.
1.6.6 Experimental Alternatives to Quantum Pharmacology
Calculations for Small Molecules: X-Ray
Crystallography and NMR SpectroscopyOver the past decade, quantum pharmacology calculations have proven to be an
immensely powerful tool in drug design and medicinal chemistry. However, several
experimental techniques offer the same information.
56 MEDICINAL CHEMISTRY
Figure 1.15 The “Butterfly Angle”. Tricyclic drugs consist of anticonvulsants (carbamazepine),
antidepressants (amitriptyline), and antipsychotics (chlorpromazine). Although all three families
consist of three interconnected ring systems, the orientation between the rings varies, imparting
a different spectrum of bioactivity.