Receptor Classes & Drug Development

RECEPTOR CLASSES &DRUG DEVELOPMENT

The existence of a specific drug receptor is usually inferred from studying the structure-activity relationship of a group of struc-turally similar congeners of the drug that mimic or antagonize its effects. Thus, if a series of related agonists exhibits identical rela-tive potencies in producing two distinct effects, it is likely that the two effects are mediated by similar or identical receptor molecules. In addition, if identical receptors mediate both effects, a competi-tive antagonist will inhibit both responses with the same K_i; a second competitive antagonist will inhibit both responses with its own characteristic K_i. Thus, studies of the relation between struc-ture and activity of a series of agonists and antagonists can identify a species of receptor that mediates a set of pharmacologic responses.

Exactly the same experimental procedure can show that observed effects of a drug are mediated by different receptors. In this case, effects mediated by different receptors may exhibit dif-ferent orders of potency among agonists and different K_i values for each competitive antagonist.

Wherever we look, evolution has created many different recep-tors that function to mediate responses to any individual chemical signal. In some cases, the same chemical acts on completely differ-ent structural receptor classes. For example, acetylcholine uses ligand-gated ion channels (nicotinic AChRs) to initiate a fast (in milliseconds) excitatory postsynaptic potential (EPSP) in postgan-glionic neurons. Acetylcholine also activates a separate class of G protein-coupled receptors (muscarinic AChRs), which mediate slower (seconds to minutes) modulatory effects on the same neurons. In addition, each structural class usually includes multiple subtypes of receptor, often with significantly different signaling or regulatory properties. For example, many biogenic amines (eg, norepinephrine, acetylcholine, and serotonin) activate more than one receptor, each of which may activate a different G protein, as previously described (see also Table 2–1). The existence of many receptor classes and subtypes for the same endogenous ligand has created important opportunities for drug development. For example, propranolol, a selective antago-nist of β adrenoceptors, can reduce an accelerated heart rate without preventing the sympathetic nervous system from causing vasocon-striction, an effect mediated by α₁ receptors.

The principle of drug selectivity may even apply to structurally identical receptors expressed in different cells, eg, receptors for steroids such as estrogen (Figure 2–6). Different cell types express different accessory proteins, which interact with steroid receptors and change the functional effects of drug-receptor interaction. For example, tamoxifen acts as an antagonist on estrogen receptors expressed in mammary tissue but as an agonist on estrogen recep-tors in bone. Consequently, tamoxifen may be useful not only in the treatment and prophylaxis of breast cancer but also in the prevention of osteoporosis by increasing bone density. Tamoxifen may also create complications in postmenopausal women, however, by exerting an agonist action in the uterus, stimulating endometrial cell proliferation.

New drug development is not confined to agents that act on receptors for extracellular chemical signals. Increasingly, pharma-ceutical chemists are determining whether elements of signaling pathways distal to the receptors may also serve as targets of selec-tive and useful drugs. We have already discussed drugs that act on phosphodiesterase and some intracellular kinases. There are several additional kinase inhibitors presently in clinical trials, as well as preclinical efforts directed at developing inhibitors of G proteins.