(on the order of 4–8 kJ/mol), and is easily overcome by thermal motion unless the
molecule is made rigid or because nonbonding interactions between functional groups
of the molecule favor one conformer over an infinite number of others. The concept
and biophysical reality of “preferred” drug conformations and their potential role in
receptor binding are currently important issues among drug designers.
For aliphatic compounds, the well-known Newman projection is used to show the
relative position of the substituents on two atoms connected to each other (as in ethane
derivatives). For example, figure 1.9 shows several possible conformers of acetyl-
choline. When the trimethylammonium-ion and acetoxy functional groups are as far
removed as possible, we speak of a fully staggeredconformation (erroneously and
confusingly also called a trans conformation). When the two groups overlap, they are
eclipsed.Between these two extremes are an infinite number of conformers called
gauche (or skew) conformersorrotamers(rotational isomers). The potential interaction
energy of the trimethylammonium-ion and acetoxy groups is lowest in the staggered
conformation and highest when the two groups are eclipsed. The stability of these
rotamers is normally opposite. An exception to this exists when two functional groups
show a favorable nonbonding interaction (e.g., hydrogen-bond formation).
Since the transition between rotamers occurs very rapidly, the existence of any one
conformer can be discussed in statistical terms only. For example, in acyclic hydrocar-
bon molecules, it has been assumed that long hydrocarbon chains exist in the staggered,
fully extended, zigzag conformation. There is, however, a considerable probability of
their also existing in skew conformations, effectively reducing the statistical length of
the carbon chain. Such considerations become important if one wishes to calculate
effective intergroup distances in drugs, which play a role in the geometric fit and bind-
ing to receptors. For instance, in the anticholinergic agents hexamethonium (1.1) and
decamethonium (1.2), the two quaternary trimethylammonium groups are connected by
six and ten methylene (-CH2-) groups, respectively.
Observations emphasize the need for extreme caution in proposing geometry-based
hypotheses when dealing with drug conformations and their correlations with receptor
structure, especially when the drug contains flexible acyclic hydrocarbon segments and
DRUG MOLECULES: STRUCTURE AND PROPERTIES 33Figure 1.9 Newman projections of acetylcholine. Rotation around torsional angles permits many
different conformers (shapes) of a molecule.