Quantitatively proteins form the most important class of drug receptors. Examples include the receptors for hormones, growth factors, transcription factors, and neurotransmitters; the enzymes of crucial metabolic or regulatory pathways (e.g., dihydrofolate reductase, acetylcholinesterase, and cyclic nucleotide phosphodiesterases); proteins involved in transport processes (e.g., Na+,K+-ATPase); secreted glycoproteins (e.g., Wnts); and structural proteins (e.g., tubulin). Specific binding properties of other cellular constituents also can be exploited for therapeutic purpose. Thus, nucleic acids are important drug receptors, particularly for cancer chemotherapeutic agents.
A particularly important group of drug receptors consists of proteins that normally serve as receptors for endogenous regulatory ligands. Many drugs act on such physiological receptors and often are particularly selective because physiological receptors are specialized to recognize and respond to individual signaling molecules with great selectivity. Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are termed agonists. Other drugs, termed antagonists, bind to receptors without regulatory effect, but their binding, blocks the binding of the endogenous agonist. Agents that are only partly as effective as agonists no matter the dose employed are termed partial agonists; those that stabilize the receptor in its inactive conformation are termed inverse agonists (Figure 1-6).
The strength of the reversible interaction between a drug and its receptor, as measured by their dissociation constant, is defined as the affinity of one for the other. Both the affinity of a drug for its receptor and its intrinsic activity are determined by its chemical structure.
CELLULAR SITES OF DRUG ACTION Drugs act by altering the activities of their receptors. The sites at which drugs act and the extent of this action are determined by the location and functional capacity of receptors. Selective localization of drug action within an organism therefore
FIGURE 1-6 Regulation of receptor activity by conformation-selective drugs. The ordinate is some activity of the receptor produced by R , the active receptor conformation (e.g., stimulation of adenylyl cyclase). If a drug D selectively binds to Ra, it will produce a maximal response. If D has equal affinity for Ri and Ra, it will not perturb the equilibrium between them and will have no effect on net activity; D would appear as an inactive compound. If the drug selectively binds to Ri, then the net amount of Ra will be diminished. If D can bind to receptor in an active conformation Ra but also bind to inactive receptor Ri with lower affinity, the drug will produce a partial response; D will be a partial agonist. If there is sufficient Ra to produce an elevated basal response in the absence of ligand (agonist-independent constitutive activity), then a drug binding to Ri will reduce activity; D will be an inverse agonist. Inverse agonists selectively bind to the inactive form of the receptor and shift the conformational equilibrium toward the inactive state. In systems that are without not constitutive activity, inverse agonists will behave like competitive antagonists. Receptors that have constitutive activity and are sensitive to inverse agonists include benzodiazepine, histamine, opioid, cannabinoid, dopamine, b adrenergic, calcitonin, bradykinin, and adenosine receptors.
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