Neurotransmission and hormonal information is extremely important for the well being of higher organisms. It is therefore not surprising that certain diseases may result from (or be associated with) anomalies in hormone- or neurotransmitter concentrations, or from the inability of their target cells to respond adequately. Administration of the messengers themselves (e.g. insulin) and of synthetic analogues is therefore often carried out to counteract these pathophysiological conditions, and in some instances also to alter normal physiological conditions (e.g. contraception). An important branch of the activities of the pharmaceutical industry is therefore implicated in the development of drugs which mimic or block the action of natural messengers:
• The agonists. These compounds bind to the receptors and elicit the physiological responses. They include the endogenous messengers and synthetic molecules.
• The antagonists or 'blockers'. These compounds are all synthetic or derived from other organisms (e.g. present in plants and animal toxins). They bind to the receptor but this interaction does not elicit the physiological response. The most common antagonists compete in a reversible fashion with the endogenous messengers for binding to their receptors, thereby preventing the target cells responding to the presence of these messengers (Figure 25). The binding sites for such competitive antagonists overlap at least in part with the binding site of the endogenous messenger.
The 'binding site' of each receptor possesses a unique spatial arrangement of amino acid residues with which certain parts of the 'Ugand' (i.e. messenger or drug) can interact. The strength of such interactions differs from one drug to another, so that the affinity of a receptor is different for every drug. The order of affinities (often called 'order of potencies') of a series of drugs for a specific receptor (i.e. its 'pharmacological profile') therefore serves as a useful 'fingerprint' for that receptor. Such fingerprints allow:
• The positive identification of a receptor.
• The discrimination of one receptor from another.
• The discovery of new receptors.
Messengers are often capable of recognizing a whole series of different receptors. These receptors are often specific for that messenger (e.g. the receptors for acetylcholine bind no other messenger), and they are usually referred to as 'receptor subtypes'. Occasionally, such a receptor family may be shared by a limited number of messengers (e.g. the adrenergic receptors can be stimulated by both adrenaline and noradrenaline, but by no other messenger).
Agonists and antagonists are of medical interest if they show pronounced affinity and selectivity towards one or more specific receptors. The discovery of such drugs usually requires the synthesis of a considerable number of structurally related molecules and the screening of their toxicity and biological activity. The derived structure-toxicity and structure-activity relationships can then be used for the design of even more efficient compounds. In the past, most of the structure-activity relationships were carried out
by measuring the drug-induced physiological responses in vivo or in intact tissues or organs. The last decades have, however, been characterized by the development of biochemical techniques such as radioligand binding and cell-based functional assays to investigate drug-receptor interactions. This allows the fast screening of the affinity of newly synthesized drugs for the receptor, or receptors, of interest. Sections B and C only deal with competitive antagonists. Alternative types of 'antagonism' (i.e. inverse agonists, allosteric and insurmountable antagonists) will be discussed later.
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