How New Developments in Pharmacology Receptor Theory Are Changing (Our Understanding of) Hypertension Therapy

Abstract

Background: Many hypertension therapeutics were developed prior to major advances in drug receptor theory. Moreover, newer drugs may take advantage of some of the newly understood modalities of receptor function.

Goal: The goal of this review is to provide an up-to-date summary of drug receptor theory. This is followed by a discussion of the drug classes recognized for treating hypertension to which new concepts in receptor theory apply.

Results: We raise ideas for mechanisms of potential new antihypertensive drugs and whether they may take advantage of new theories in drug-receptor interaction.

Keywords: agonist; antagonist; blood pressure; constitutive activity; drug receptor theory; drug–receptor interaction; hypertension; inverse agonist.

Figure 1.

Time line of development/first use of antihypertensive therapies. Both individual and drug classes are named in the light green shaded boxes. The colorless boxes have the potential to be used as antihypertensives or to be discovered. Adapted from Kotchen 2011.

Figure 2.

(a) Depiction of the four (4) major classes of receptors recognized by pharmacologists. (b) Depiction of the difference in site of action of an orthosteric agonist (orange circle) and allosteric modulator (purple shape).

Figure 3.

(a) Cartoon of basic drug receptor theory. The agonist (orange circle) is in equilibrium with the receptor and can move forward with biological action (change of receptor from blue to purple). (b) Depiction of receptor constitutive activity, where receptor can effect biological function in the absence of ligand.

Figure 4.

(a) Comparison of the magnitude of biological effect (stacked bars) between a full agonist (green), partial agonist (blue) and antagonist (burgundy). Stacked bars compare the magnitude of the biological effect observed in the presence of these agonist. (b) Depiction of biased agonism. Different ligands (gray, brown, burgundy), have the ability to elicit a different biological effect based on how they stimulate the signal transduction available to that receptor (effector A, effector B). Stacked bars below are colored differently to indicate that the effect elicited by these three different ligands—ligand biased to effector A, unbiased ligand, biased ligand to effector B—is different in outcome.

Figure 5.

(a) Pharmacological parameters (threshold, EC50, Maximum) that can be derived from a concentration response curve (typically carried out in vitro). (b) Pharmacological parameters (threshold, ED50, Maximum) that can be derived from a dose response curve (typically carried out in vivo). (c) Depiction of how a positive allosteric modulator (green; PAM) and negative allosteric modulator (red; NAM) might change a concentration response curve (black line = control curve).

Figure 6.

Comparison of the baseline effects of the four classes of ligands described in this review. On the y-axis is the effect of these ligands elicited on their own.