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

• 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.

Ämnesord

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

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

Nyckelord

Adminstration

Oral

Animals

Antihypertensive Agents/chemical synthesis/chemistry/pharmacology

Bicarbonates/metabolism

Biological Availability

Cell Line

Drug Design

Enzyme Activation

Female

Half-Life

Intestinal Mucosa/metabolism

Liver/metabolism

Male

Mitogen-Activated Protein Kinases/metabolism

Molecular Mimicry

Neurites/drug effects/physiology

Peptides/chemistry

Radioligand Assay

Rats

Rarts

Inbred SHR

Rats

Sprague-Dawley

Receptor

Angiotensin

Type 2/*antagonists/metabolism

Sulfonamides/*chemical synthesis/chemistry/pharmacology

Swine

Thiophenes/*chemical synthesis/chemistry/pharmacology

Uterus/metabolism

Administration; Oral

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)