Abstract
The Bradykinin (BK) B2 receptor (B2R) is integral to the regulation of endothelium-dependent blood pressure and pain pathophysiology. This study investigated the biased properties of three novel BK analogs on B2R-triggered signaling pathways, focusing on their propensity for either G-protein or β-arrestin pathways. The analogs were designed to explore specific characteristics of the different signaling pathways they activate with greater potency. Three analogs were selected for their unique properties and ability to bias B2 receptor signaling towards distinct pathways. Using BRET-based tools, we showed that analog Thi5,8-BK exhibited balanced agonism, resembling BK profile. Analog Thi5,Trp8-BK displayed biased agonism towards β-arrestin recruitment, and analog D-Arg0-Hyp3-Thi5,8-BK was biased towards Gq protein activation.
To assess the physiological effects of these new compounds on the cardiovascular system, we evaluated the impact of BK and its analogs on blood pressure at a dose of 50 nmoles/injection and varying doses in Wistar rats. Thi5,8-BK mirrored BK in reducing blood pressure, while D-Arg0-Hyp3-Thi5,8-BK, the Gq-biased analog, demonstrated significantly higher potency in lowering blood pressure, with substantial effects even at 12.5 nmoles/injection. In contrast, Thi5-Trp8-BK, biased towards the β-arrestin pathway, showed the least reduction in blood pressure across tested doses.
Effects of the compounds on pain signaling pathways were also explored, measuring lick duration after a nociceptive stimulus in Wistar rats. High doses of BK consistently desensitized pain response, a trait also observed for D-Arg0-Hyp3-Thi5,8-BK due to its enhanced Gq protein activation potency, and Thi5,8-BK, the balanced agonist. Interestingly, Thi5-Trp8-BK maintained pain stimulus even at high doses that typically lead to BK desensitization, highlighting β-arrestin involvement in this phenomenon.
Additionally, we determined the affinities of the BK analogs for B2R and their ability to activate different signaling pathways for deeper pharmacological characterization. This study not only advances our understanding of B2 receptor complexities but also aids in developing targeted therapeutics for hypertension and pain management.
To assess the physiological effects of these new compounds on the cardiovascular system, we evaluated the impact of BK and its analogs on blood pressure at a dose of 50 nmoles/injection and varying doses in Wistar rats. Thi5,8-BK mirrored BK in reducing blood pressure, while D-Arg0-Hyp3-Thi5,8-BK, the Gq-biased analog, demonstrated significantly higher potency in lowering blood pressure, with substantial effects even at 12.5 nmoles/injection. In contrast, Thi5-Trp8-BK, biased towards the β-arrestin pathway, showed the least reduction in blood pressure across tested doses.
Effects of the compounds on pain signaling pathways were also explored, measuring lick duration after a nociceptive stimulus in Wistar rats. High doses of BK consistently desensitized pain response, a trait also observed for D-Arg0-Hyp3-Thi5,8-BK due to its enhanced Gq protein activation potency, and Thi5,8-BK, the balanced agonist. Interestingly, Thi5-Trp8-BK maintained pain stimulus even at high doses that typically lead to BK desensitization, highlighting β-arrestin involvement in this phenomenon.
Additionally, we determined the affinities of the BK analogs for B2R and their ability to activate different signaling pathways for deeper pharmacological characterization. This study not only advances our understanding of B2 receptor complexities but also aids in developing targeted therapeutics for hypertension and pain management.
| Translated title of the contribution | Diseño, Síntesis y Caracterización Farmacológica de Nuevos Análogos de Bradicinina. |
|---|---|
| Original language | English |
| State | Submitted - 6 Sep 2024 |
| Event | Bradykinin Symposium - Berlin, Alemania, Berlin, Germany Duration: 5 Sep 2024 → 6 Sep 2024 |
Conference
| Conference | Bradykinin Symposium |
|---|---|
| Country/Territory | Germany |
| City | Berlin |
| Period | 5/09/24 → 6/09/24 |