regulation, respectively, but they are also probably different in a morphological sense: the
neuromodulatory receptors are assumed to be presynaptic, or situated on the presynaptic
terminal membrane ahead of the synaptic gap, whereas other receptors are the classical
postsynapticreceptors, embedded in the postsynaptic membrane of the effector cell or of
the next neuron. In the first case, the receptor modulates neurotransmitter release; in the
second, it may activate an enzyme such as adenylate cyclase, or trigger an action poten-
tial. As we shall see later, almost all neurotransmitters show receptor multiplicity, and
medicinal chemists deal with multiple adrenergic receptor subtypes and many different
opiate receptors, just to name two examples.
Receptor plasticity could be invoked as the underlying common trait of multiple
receptors. For example, although the multiple adrenergic isoreceptors are similar, they
react to the common neurotransmitter norepinephrine (2.4) in a quantitatively different
manner. They also show a drug specificity that varies from organ to organ and differs
in various species of animals. In subsequent chapters of this book, receptor multiplicity
as the rule rather than the exception will become amply evident. It is to be hoped that,
in time, the comparison of isoreceptor molecular structures will provide precise criteria
for their differentiation.
The multiplicity of receptor or recognition sites for agonists and antagonists is well
documented. One may distinguish (i) agonist binding sites, (ii) competitive antagonist
binding sites (accessory sites), and (iii) noncompetitive antagonist or regulatory bind-
ing sites (allosteric sites).
Theagonist binding site is the subject of continuous discussion throughout this book,
ranging from a purely physical approach to the treatment of its biochemical character-
istics, where these are known. In this discussion, it is implicit that we are dealing with
discrete loci on the receptor macromolecule: specific amino acids, lipids, or nucleotides
held in just the right geometric configuration by the scaffold of the rest of the molecule,
as well as by its supramolecular environment such as a membrane.
Competitive antagonists were originally assumed to bind to the agonist binding site
and, in some way, displace and exclude the agonist as a result of their very high affin-
ity but lack of intrinsic activity. This behavior would result in displaced but parallel
dose–response curves. Our present views are at variance with such simplistic older
ideas. The mere fact of great chemical dissimilarity between agonists and competitive
antagonists in the vast field of neurotransmitters precludes identity of the two receptor
sites. It is evident at a glance that a careful analysis is needed to discern correlations
between agonist–antagonist pairs or even between antagonists of the same class. As
always, there are notable exceptions to this. For example, opiate analgesics and their
86 MEDICINAL CHEMISTRY