Novel and potent small-molecule urotensin II receptor agonists

A series of analogs of the non-peptidic urotensin II receptor agonist N-[1-(4-chlorophenyl)-3-(dimethylamino)propyl]-4-phenylbenzamide (FL104) has been synthesized and evaluated pharmacologically. The enantiomers of the two most potent racemic analogues were obtained from the corresponding diastereo...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-07, Vol.17 (13), p.4657-4665
Main Authors: Lehmann, Fredrik, Currier, Erika A., Clemons, Bryan, Hansen, Lars K., Olsson, Roger, Hacksell, Uli, Luthman, Kristina
Format: Article
Language:English
Subjects:
Agonists
Animals
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - pharmacology
Biological and medical sciences
Crystallography, X-Ray
Humans
Medical sciences
Mice
Models, Molecular
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
NIH 3T3 Cells
Parallel synthesis
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
R-SAT
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
SAR
Structure-Activity Relationship
Urotensin II
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Summary:A series of analogs of the non-peptidic urotensin II receptor agonist N-[1-(4-chlorophenyl)-3-(dimethylamino)propyl]-4-phenylbenzamide (FL104) has been synthesized and evaluated pharmacologically. The enantiomers of the two most potent racemic analogues were obtained from the corresponding diastereomeric mandelic amides. In agreement with previously observed SAR, most of the agonist potency resided in the ( S) enantiomers. The most potent UII receptor agonist in the new series was ( S)- N-[3-dimethylamino-1-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide (EC 50 = 23 nM at the urotensin II receptor).
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.04.062