168 Heterocycles in Medicine
Drugs exert their effects by a number of mechanisms, the most important being:
(a) Mimicking or opposing the effects of physiological hormones or neurotransmitters. Compounds that mimic the
effect of the natural agent are known as agonists, those that oppose are known as antagonists. These drugs act by
binding at a receptor – the site where the natural physiological agent binds. This receptor is usually a specifi c
domain of a protein molecule comprising part of a cell.
(b) Interaction with enzymes, usually by inhibition. This generally occurs by binding at the active site of the enzyme
(where the substrate binds), in a very similar manner to receptor binding – the comments shown below, concerning
receptors, can equally be applied to enzyme interactions with drugs.
(c) Modifying natural macromolecules such as DNA and RNA either by direct interaction or by the incorporation of
synthetic analogues of structural components (e.g. one of the heterocyclic bases) into the polymer.
- Binding at the receptor may be competitive (i.e. the drug is in equilibrium/exchange with the natural agent) or,
in others, it can be non-competitive – fi rmly bound with no exchange. - Receptors usually exist as a number of subtypes, often with further subdivisions, which mediate different physi-
ological effects by interaction with the single natural agent. The key to a successful drug very often depends on
devising a molecule that has a selective interaction with just one subtype. - Sometimes, binding at a site other than at the normal receptor (allosteric binding) can be the mechanism of
action – the remote binding alters the shape of the protein as a whole and hence infl uences the receptor. - Binding/action at the receptor is often only the start of a complex cascade of actions within the cell.
- The mechanisms of binding to the receptor can be essentially physical (H-bonding, or attractions via ionic or Van der
Waals forces, etc.), with several points of interaction, or it may be covalent (e.g. N-alkylation) and thus irreversible.
In this book we are concerned with heterocycles, so the coverage in what follows does not necessarily refl ect the relative
medical importance of different areas. Complete coverage of all areas of signifi cance is obviously impossible but the
aim is to give an appreciation of the wide-ranging importance of heterocycles in medicine.
Drug discovery
There are a number of stages in the ‘invention’ and commercialisation of a drug, and chemistry is very heavily involved in
the early stages of discovery, design and process development. Also, later chemical investigations are concerned with the
absorption and metabolism of the drug in the body. After the drug is marketed there is also a signifi cant role to play in
the detection of fraud and ‘forgery’ , which, unfortunately, are not uncommon in today’s international medicines market.
A traditional logical approach to drug design involves the synthesis of compounds that are structurally similar to the
natural agent, with alterations of substituents or variations in the electronic nature or precise shape of any aromatic
rings (a key asset of heterocycles!). Modifi cations using heterocycles can also be used to give favourable physical