The first strategy concerns the optimal number of contact points between the drug and
the receptor. If the drug molecule has only two functional groups capable of binding to
a receptor, then the interaction lacks specificity; such a drug could interact with too many
putative receptors and would probably demonstrate unwanted toxicities. On the other
hand, if the drug molecule has too many functional groups capable of interaction with a
receptor, the molecule tends to be too polar and is thus too poorly absorbed and too
rapidly excreted. Also, such a highly polar molecule will not likely cross the blood–brain
barrier. Therefore, when designing a drug, an average of 3–5 points of contact between
the drug and the receptor tends to be optimal; this corresponds to the drug molecule con-
taining 3–5 functional groups capable of establishing binding interactions with the
receptor macromolecule. If the drug is to cross the blood–brain barrier, then fewer con-
tact points may be required; if the drug is to stay confined to the gastrointestinal tract and
not absorbed, then more contact points may be tolerated.
The second strategy concerns the selection of functional groups capable of enabling
the most energetically desirable interaction with the receptor site. As stated, polar
groups tend to give the most energetically favorable binding interactions. Ionic interac-
tions, for example, are among the strongest. However, desirable though they may be,
too many polar groups make the drug molecule too hydrophilic, causing poor absorp-
tion, rapid excretion, and poor distribution. Usually, a mixture of varying functional
groups with varying properties is desirable. If the drug is to cross the blood–brain bar-
rier, incorporating lipophilic groups (such as aromatic rings capable of both lipophilic
interactions and charge transfer interactions) into the drug molecule satisfies the
twofold role of adding a point of contact between the drug and the receptor and of
increasing the lipophilicity of the drug so that it can diffuse into the brain.
The drug designer must select functional groups from the following interaction types
to be incorporated into the drug molecule: ionic interactions (e.g., carboxylate,
sulphonate, phosphate, ammonium); dipole–dipole interactions (e.g., carbonyl, thiocar-
bonyl, hydroxyl, thiol, amine); hydrogen-bonding donors and acceptors (e.g., carbonyl,
thiocarbonyl, hydroxyl, thiol, amine); charge transfer interaction (e.g., heteroaromatics,
aromatics), or hydrophobic interactions (e.g., tert-butyl, sec-butyl). Initially, these
groups are selected to enable an optimal pharmacodynamic interaction with the drug
receptor macromolecule. However, these functional groups may also be selected to
influence the pharmacokinetic and pharmaceutical properties of the drug molecule.
Highly polar functional groups will facilitate renal excretion; lipophilic functional
groups will promote passive diffusion across the blood–brain barrier.
2.4 DEFINITIONS OF CLASSICAL BINDING TERMS FOR
DRUG–RECEPTOR INTERACTIONS
The findings of classical pharmacology serve as a basis for a discussion of drug–receptor
interactions at a biological level. To aid in this discussion, some classical pharmaco-
logical binding terms are briefly defined. The traditional dose–response curve is central
to these discussions, and a representative example is given in figure 2.2.
Anagonist is a substance that interacts with a specific cellular constituent, the receptor,
and elicits an observable biological response. An agonist may be an endogenous
physiological substance such as a neurotransmitter or hormone, or it can be an exogenous
substance such as a synthetic drug.
RECEPTORS: STRUCTURE AND PROPERTIES 75