Receptors are macromolecules involved in chemical signaling between and within cells; they may be located on the cell surface membrane or within the cytoplasm (see Table 1: Pharmacodynamics: Some Types of Physiologic and Drug-Receptor Proteins). Activated receptors directly or indirectly regulate cellular biochemical processes (eg, ion conductance, protein phosphorylation, DNA transcription, enzymatic activity). Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands. A ligand may activate or inactivate a receptor; activation may increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes. Few if any drugs are absolutely specific for one receptor or subtype, but most have relative selectivity. Selectivity is the degree to which a drug acts on a given site relative to other sites; selectivity relates largely to physicochemical binding of the drug to cellular receptors.

Table 1
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Some Types of Physiologic and Drug-Receptor Proteins Type Structure Cellular Location Examples Multisubunit ion channels Cell surface transmembrane Acetylcholine (nicotinic) GABAA Glutamate Glycine G-protein– coupled receptors Cell surface transmembrane Acetylcholine (muscarinic) α- and β-adrenergic receptor proteins Eicosanoids Protein kinases Cell surface transmembrane Growth factors Insulin Peptide hormones Transcription factors Cytoplasm Steroid hormones Thyroid hormone Vitamin D GABA = γ-aminobutyric acid; GDP = guanosine diphosphate; GTP = guanosine triphosphate.

A drug's ability to affect a given receptor is related to the drug's affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which a ligand activates receptors and leads to cellular response). A drug's affinity and activity are determined by its chemical structure.

Physiologic functions (eg, contraction, secretion) are usually regulated by multiple receptor-mediated mechanisms, and several steps (eg, receptor-coupling, multiple intracellular 2nd messenger substances) may be interposed between the initial molecular drug-receptor interaction and ultimate tissue or organ response. Thus, several dissimilar drug molecules can often be used to produce a desired response.

Ability to bind to a receptor is influenced by external factors as well as by intracellular regulatory mechanisms. Baseline receptor density and the efficiency of stimulus-response mechanisms vary from tissue to tissue. Drugs, aging, genetic mutations, and disorders can increase (up-regulate) or decrease (down-regulate) the number and binding affinity of receptors. For example, clonidineSome Trade Names
CATAPRES
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down-regulates α₂-receptors; thus, rapid withdrawal of clonidineSome Trade Names
CATAPRES
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can cause hypertensive crisis. Chronic therapy with β-blockers up-regulates β-receptor density; thus, severe hypertension or tachycardia can result from abrupt withdrawal. Receptor up-regulation and down-regulation affect adaptation to drugs (eg, desensitization, tachyphylaxis, tolerance, acquired resistance, postwithdrawal supersensitivity).

Ligands bind to precise molecular regions, called recognition sites, on receptor macromolecules. The binding site for a drug may be the same as or different from that of an endogenous agonist (hormone or neurotransmitter). Agonists that bind to an adjacent site or a different site on a receptor are sometimes called allosteric agonists. Nonspecific drug binding also occurs—ie, at molecular sites not designated as receptors (eg, plasma proteins). Drug binding to such nonspecific sites prohibits the drug from binding to the receptor and thus inactivates the drug. Unbound drug is available to bind to receptors and thus have an effect.

Agonists and antagonists: Agonist drugs activate receptors to produce the desired response. Conventional agonists increase the proportion of activated receptors. Inverse agonists stabilize the receptor in its inactive conformation and act similarly to competitive antagonists (see Pharmacodynamics: Agonists and antagonists). Many hormones, neurotransmitters (eg, acetylcholine, histamine, norepinephrine), and drugs (eg, morphineSome Trade Names
DURAMORPH
MS CONTIN
MSIR
ROXANOL
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, phenylephrineSome Trade Names
NEO-SYNEPHRINE
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, isoproterenolSome Trade Names
ISUPREL
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) act as agonists.

Antagonists prevent receptor activation. Preventing activation has many effects. Antagonist drugs increase cellular function if they block the action of a substance that normally decreases cellular function. Antagonist drugs decrease cellular function if they block the action of a substance that normally increases cellular function.

Receptor antagonists can be classified as reversible or irreversible. Reversible antagonists readily dissociate from their receptor; irreversible antagonists form a stable, permanent or nearly permanent chemical bond with their receptor (eg, by alkylation). Pseudo-irreversible antagonists slowly dissociate from their receptor.

In competitive antagonism, binding of the antagonist to the receptor prevents binding of the agonist to the receptor. In noncompetitive antagonism, agonist and antagonist can be bound simultaneously, but antagonist binding reduces or prevents the action of the agonist. In reversible competitive antagonism, agonist and antagonist form short-lasting bonds with the receptor, and a steady state among agonist, antagonist, and receptor is reached. Such antagonism can be overcome by increasing the concentration of the agonist. For example, naloxoneSome Trade Names
NARCAN
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(an opioid receptor antagonist that is structurally similar to morphineSome Trade Names
DURAMORPH
MS CONTIN
MSIR
ROXANOL
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), when given shortly before or after morphineSome Trade Names
DURAMORPH
MS CONTIN
MSIR
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, blocks morphineSome Trade Names
DURAMORPH
MS CONTIN
MSIR
ROXANOL
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's effects. However, competitive antagonism by naloxoneSome Trade Names
NARCAN
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can be overcome by giving more morphineSome Trade Names
DURAMORPH
MS CONTIN
MSIR
ROXANOL
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.

Structural analogs of agonist molecules frequently have agonist and antagonist properties; such drugs are called partial (low-efficacy) agonists, or agonist-antagonists. For example, pentazocineSome Trade Names
TALWIN
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activates opioid receptors but blocks their activation by other opioids. Thus, pentazocineSome Trade Names
TALWIN
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provides opioid effects but blunts the effects of another opioid if the opioid is given while pentazocineSome Trade Names
TALWIN
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is still bound. A drug that acts as a partial agonist in one tissue may act as a full agonist in another.

Last full review/revision November 2007 by Angela Cafiero Moroney, PharmD

Content last modified February 2012