The Cardiovascular Regulators

In the US, researchers from the Institute of City of Hope and Canada McGill University have revealed how new drugs could interact with receptors on the cell surface to manipulate cardiovascular regulation (1).

We speak with Stephane Laporte, lead author and professor of endocrinology and metabolism from the department of medicine at McGill University, to learn more…

G protein-coupled receptors (GPCRs), such as angiotensin II (AngII) type 1 receptor (AT1R), account for approximately 30 percent of prescribed medications. However, limited understanding of how drugs interact with receptors to activate or inhibit specific cellular pathways leads to challenges in drug development. Despite drugs being designed to only target one subtype of GPCR, they often affect other receptors and lead to unwanted side effects.

Targeting allosteric sites allows for more precise control over the hormonal tone and responses – and greater selectivity in drug action. With regards to AT1R, there are known antagonists on the orthosteric site, but there is no identified druggable allosteric site on this receptor. Accordingly, we set out to identify specific structural elements within the receptor where small molecules could bind in an allosteric fashion and provide a new way to modulate AT1R’s response. We also wanted to gain insights into how drugs – both orthosteric and allosteric – transmit information through the receptor to either activate or inhibit specific cellular pathways (a phenomenon known as bias signaling). I believe that this knowledge could be instrumental in designing more effective drugs.

AT1R is responsible for controlling various physiological functions, including blood volume regulation via the kidney for water excretion/retention and vasculature contraction. When the AT1R in blood vessels activates, it releases important mediators in cells, specifically inositol triphosphate and calcium. This activation, in turn, causes the cells to contract and contributes to elevated blood pressure. Medications like angiotensin II receptor inhibitors (ARBs) work by blocking this receptor by out competing the hormone angiotensin II. In doing so, they reduce blood pressure and alleviate the workload on the heart. 

ARBs achieve their antihypertensive effect by reducing peripheral vascular resistance – an action that decreases both cardiac afterload and preload. Though it is important to acknowledge that angiotensin II, beyond its impact on blood pressure, could perform a mechanistic role in promoting cardiovascular diseases by acting directly on the heart tissue. In fact, pre-clinical models have demonstrated that angiotensin II can induce cardiac hypertrophy and remodeling even in situations where blood pressure remains within normal limits. Merely targeting peripheral blood pressure with ARBs may not be sufficient. 

To address this, there is a need to directly target the AT1R in the heart itself, acknowledging its role in cardiac pathologies beyond its effects on blood pressure regulation. Blocking the AT1R in the heart may not be sufficient in the long run because the receptor activity also plays a protective role on cardiomyocytes, the cells that compose the heart and control contraction (one could describe this as the “yin and yang” effect of angiotensin II). 

Our team believes that drugs acting on AT1R that preserve the protective signaling function in the heart and block its contractile function in the vessels and the remodeling function in the heart would be better than ARBs, which simply block all AT1Rs functions in cells.

Treating cardiovascular conditions (hypertension and congestive heart failure) is not inherently challenging – and there are a wide array of drugs at our disposal. However, solely managing blood pressure might not suffice to prevent heart failure. To effectively combat this condition, we must employ a combination of therapies that target different aspects of the problem. 

However, clinical studies have revealed that, even when using AT1R blockers in either single or multiple drug regimens with other classes of drugs, some patients still experience heart failure despite treatments. Additionally, certain ARBs have demonstrated long-term adverse effects and contraindications in some conditions (for example, preeclampsia). 

Other than controlling blood pressure, there is currently no established therapy for a particular type of heart failure characterized by preserved ejection fraction. Although there are new drugs targeting AT1R under investigation, they often share structural similarities with angiotensin II and have limited in vivo effectiveness because of their short duration of action. 

We uncovered the intricate allosteric communication within the receptor, which dictates receptor responses to certain intracellular pathways, which may lead to bias signaling regulation. The breakthrough of our study lies in the revelation of previously unknown regions in the receptor (beyond the hormone binding site) that regulate the transmission of vital information to cellular effectors. 

This discovery opens exciting possibilities for developing new allosteric drugs that can precisely modulate the receptor’s activity in cardiovascular diseases, as well as for other receptors of this family.

We aim to harness the potential of these newly discovered allosteric sites to create drugs with unique therapeutic properties. We have already identified promising candidates that bind to these sites and exhibit the expected behavior by selectively activating specific cellular pathways over the other. Now, our goal is to refine and develop these candidates into novel drugs that could offer significant benefits, particularly in the context of heart failure.

We also hope that some of these drug candidates may prove effective in addressing preeclampsia, a condition where AT1R dysregulation is common and where conventional ARBs are not suitable for pregnant women due to contraindications.