Dimerix demonstrates that angiotensin ligand effects through heterodimers may not be blocked by marketed angiotensin receptor blockers (ARBs). Dimerix has novel and known angiotensin heterodimers.
Assessing effect of Angiotensin Receptor Blockers (ARBs) on Angiotensin II AT1R Heterodimers
Downloadable Version: Non-Confidential Fact Sheet (PDF)
Dimerix’s GPCR-HIT Technology tested the blocking effect of some marketed ARBs1 against the angiotensin monomer (or homodimer) and two different angiotensin heterodimers demonstrating (a) different blocking responses for monomer versus one of the heterodimers tested; and (b) failure of ARBs to attenuate certain angiotensin heterodimer responses (see Heterodimer #2).
Formation of heterodimers leading to hypersensitization has been shown with heterodimer combinations, including angiotensin heterodimers2. Dimerix GPCR-HIT has been used to show hypersensitization for an angiotensin heterodimer with dual treatment having a substantially greater than additive effect. Moreover, the EC50 (3nM) for ATII activation of the AT1R heterodimer response is suitable for compound screening.
1Marketed angiotensin antagonists include: valsartan – Diovan (Novartis); losartan – Cozaar (Merck); irbesartan – Avapro (Bristol-Myers-Squibb); candesartan – Atacand (Astra Zeneca); olmesartan medoxomil – Benicar (Sankyo Pharma); telmisartan – Micardis (Boehringer Ingelheim), Pritor/Kinzal (Bayer Schering Pharma), Telma (Glenmark Pharma), Teleact D (Ranbaxy).
2Hilairet et al. (2003) Hypersensitization of the orexin 1 receptor by the CB1 receptor, Journal of Biological Chemistry 278:23731-23737.
