Development of selective non-peptide angiotensin II type 2 receptor agonsists

• The development of the first drug-like selective angiotensin II type 2 (AT(2)) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT(1)) receptor/AT(2) receptor agonist L-162,313 is presented. Compound 22 with a K-i value of 0.4 nM for the AT(2) receptor and a K-i > 10 mu M for the AT(1) receptor induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhancesin vivo duodenal alkaline secretion in Sprague-Dawley rats and lowers the mean arterial blood pressure in anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. In addition, Compound 22 has a bioavailability of 20-30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT(2) receptor in more detail.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

angiotensin

AT(2) receptor

AT(2) receptor agonist

drug development

medical chemistry

PHARMACY

FARMACI

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