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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antihypertensive Agents / chemical synthesis
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Antihypertensive Agents / chemistry
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Antihypertensive Agents / pharmacology
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Bicarbonates / metabolism
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Biological Availability
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Cell Line
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Drug Design
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Enzyme Activation
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Female
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Half-Life
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In Vitro Techniques
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Intestinal Mucosa / metabolism
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Liver / metabolism
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Male
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Mimicry
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Neurites / drug effects
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Neurites / physiology
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Peptides / chemistry
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Radioligand Assay
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Rats
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Rats, Inbred SHR
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Rats, Sprague-Dawley
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Receptor, Angiotensin, Type 2 / agonists*
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Receptor, Angiotensin, Type 2 / metabolism
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Swine
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Uterus / metabolism
Substances
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Antihypertensive Agents
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Bicarbonates
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N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide
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Peptides
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Receptor, Angiotensin, Type 2
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Sulfonamides
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Thiophenes
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Mitogen-Activated Protein Kinases