Other drugs act as pharmacologic antagonists; that is, they bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor. Some of the most useful drugs in clinical medicine are pharmacologic antagonists. Still other drugs bind to a different site on the receptor than that bound by endogenous ligands; such drugs can produce useful and quite different clinical effects by acting as so-called allosteric modulators of the receptor.
Most receptors for clinically relevant drugs, and almost all of the receptors that we discuss in this chapter, are proteins. Traditionally, drug binding was used to identify or purify receptor proteins from tissue extracts; consequently, receptors were discovered after the drugs that bind to them. Advances in molecular biology and genome sequencing made it possible to identify receptors by predicted structural homology to other (previously known) receptors. This effort revealed that many known drugs bind to a larger diversity of receptors than previously anticipated and motivated efforts to develop increasingly selective drugs. It also identified a number of orphan receptors, so-called because their natural ligands are presently unknown; these may prove to be useful targets for future drug development.
The best-characterized drug receptors are regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones. This class of receptors mediates the effects of many of the most useful therapeutic agents. The molecular structures and biochemical mechanisms of these regulatory receptors are described in a later section entitled Signaling Mechanisms & Drug Action.
Other classes of proteins have been clearly identified as drug receptors. Enzymes may be inhibited (or, less commonly, activated) by binding a drug. Examples include dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate; 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase, the receptor for statins; and various protein and lipid kinases. Transport proteins can be useful drug targets. Examples include Na+/K+-ATPase, the membrane receptor for cardioactive digitalis glycosides; norepinephrine and serotonin transporter proteins that are membrane receptors for antidepressant drugs; and dopamine transporters that are membrane receptors for cocaine and a number of other psychostimulants. Structural proteins are also important drug targets, such as tubulin, the receptor for the anti-inflammatory agent colchicine.
This chapter deals with three aspects of drug receptor function, presented in increasing order of complexity: (1) receptors as determinants of the quantitative relation between the concentration of a drug and the pharmacologic response, (2) receptors as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs, and (3) receptors as key determinants of the therapeutic and toxic effects of drugs in patients.
The relation between dose of a drug and the clinically observed response may be complex. In carefully controlled in vitro systems, however, the relation between concentration of a drug and its effect is often simple and can be described with mathematical precision. It is important to understand this idealized relation in some detail because it underlies the more complex relations between dose and effect that occur when drugs are given to patients.
Concentration-Effect Curves & Receptor Binding of Agonists
Even in intact animals or patients, responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved. This relation between drug concentration and effect is traditionally described by a hyperbolic curve (Figure 2–1A) according to the following equation: where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produces 50% of maximal effect.