Heterocycles in Medicine 169properties, for example replacing a benzene ring by a pyridine ring may improve aqueous solubility. However, a
surprising number of biologically active substances bear only a tenuous (or no!) structural similarity to the natural
agent/transmitter. An excellent illustration is the well-known indole alkaloid strychnine, which is a competitive
antagonist of the Central Nervous System (CNS) neurotransmitter glycine!
Other routes to drug discovery include isolation and screening of compounds (‘natural products’) from natural sources
that may have been reported in folklore to have medicinal properties, the fortuitous discovery of unexpected activity in a
compound being investigated in another disease area (Viagra is an example) and the crude but reasonably effective method
of screening large numbers of random compounds synthesised by combinatorial chemistry (the rapid synthesis of a large
number of different but structurally related molecules by varying substituents at ‘points of diversity’ on a template). When
a ‘lead compound’ has been obtained by one of these methods, more rational optimisation can be carried out.
Drug development
One key to commercialising a drug is a good chemical synthesis, which is highly reproducible in chemistry and product
purity. It must also be produced to a target price – this varies greatly depending on a number of factors, including potency,
that is, it relates to the amount of the chemical substance used in the fi nal formulation, such as in tablets. This is the most
demanding area for the chemist. Yields for steps in a process are very frequently increased dramatically by intensive proc-
ess research – improving literature reactions with reported yields of 20–30% up to a usable 80–90% is not uncommon.
The neurotransmitters
The major neurotransmitters shown below act in both the peripheral system (the muscles, blood vessels and organs) and
central nervous system (CNS), which comprises the brain and spinal cord. These neurotransmitters include heterocyclic
(histamine, 5-hydroxytryptamine) and non-heterocyclic substances (catecholamines: adrenaline, noradrenaline, and
dopamine; acetyl choline). The CNS also has other important neurotransmitters, including the amino acids glycine,
glutamic acid, and GABA (-aminobutyric acid, H 2 N(CH 2 ) 3 CO 2 H).
The CNS and peripheral systems are separated by the blood–brain barrier, which stands between the blood stream and the
brain tissue – it is essentially the walls of the brain’s blood vessels, which are different to those in the periphery. A complex
combination of physical factors, such as lipophilicity/polarity, molecular weight and active transport systems, determines
the ability of molecules to cross the blood–brain barrier and thus gain access to the CNS. The consideration as to whether a
drug can or cannot reach the brain is always an important design consideration – drugs acting on the CNS obviously need to
reach it but for peripherally-acting drugs, the opposite is required – keeping them out may be essential to avoid side-effects.