Novel small molecule neurotensin antagonists: 3-(1,5-diaryl-1,5-dioxopentan-3-yl)benzoic acids

• Published in: Bioorganic & medicinal chemistry letters Vol. 7; no. 5; pp. 561 - 566
• Main Authors: Johnson, S.J., Akunne, H.C., Heffner, T.G., Kesten, S.R., Pugsley, T.A., Wise, L.D., Wustrow, D.J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 04-03-1997; Elsevier
• Subjects: Biological and medical sciences; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Rodentia; Central nervous system; Diketone; Neurotensin; In vitro; Vertebrata; Mammalia; Structure activity relation; Mouse; Carboxylic acid; Animal; Peptidergic receptor; Benzenic compound; Antagonist; Chemical synthesis; Brain (vertebrata)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(97)00067-X

Screening in a neurotensin (NT) receptor binding assay resulted in the discovery of compound
1 with NT receptor binding affinity of 450 nM. SAR studies that varied substituents on each aromatic ring and the linking 1,5-pentanedione chain lead to compound
39 with 42 nM affinity. The more potent compounds were shown to be NT antagonists by their ability to inhibit NT induced calcium mobilization in HT29 cells.
Screening in a neurotensin (NT) receptor binding assay resulted in the discovery of compound
1 with NT receptor binding affinity of 450 nM. SAR studies that varied substituents on each aromatic ring and the linking 1,5-pentanedione chain lead to compound
39 with 42 nM affinity. The more potent compounds were shown to be NT antagonists by their ability to inhibit NT induced calcium mobilization in HT29 cells.