2. Academic Validation
  3. Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist

Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist

  • J Med Chem. 2004 Nov 18;47(24):5995-6008. doi: 10.1021/jm049715t.
Yiqian Wan 1,  Charlotta Wallinder,  Bianca Plouffe,  Hélène Beaudry,  A K Mahalingam,  Xiongyu Wu,  Berndt Johansson,  Mathias Holm,  Milad Botoros,  Anders Karlén,  Anders Pettersson,  Fred Nyberg,  Lars Fändriks,  Nicole Gallo-Payet,  Anders Hallberg,  Mathias Alterman
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
PMID: 15537354 DOI: 10.1021/jm049715t
Abstract

The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.

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