Replacement of the quinoline system in 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonists

• Published in: Farmaco (Società chimica italiana : 1989) 1999-06, Vol.54 (6), p.364-374
• Main Authors: Giardina, G.A.M, Artico, M, Cavagnera, S, Cerri, A, Consolandi, E, Gagliardi, S, Graziani, D, Grugni, M, Hay, D.W.P, Luttmann, M.A, Mena, R, Raveglia, L.F, Rigolio, R, Sarau, H.M, Schmidt, D.B, Zanoni, G, Farina, C
• Format: Article
• Language: English
• Subjects: 2-Phenyl-4-quinolinecarboxamides; Animals; Binding, Competitive - drug effects; Biological and medical sciences; CHO Cells; Cloning, Molecular; Cricetinae; Humans; Medical sciences; Neurokinin B; Neurokinin-3 receptor antagonists; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - pharmacology; Radioligand Assay; Receptors, Neurokinin-3 - antagonists & inhibitors; Structure-Activity Relationship; Tachykinins
• ISSN: 0014-827X; 1879-0569
• DOI: 10.1016/S0014-827X(99)00043-9

Results from a medicinal chemistry approach aimed at replacing the quinoline ring system in the potent and selective human neurokinin-3 (hNK-3) receptor antagonists 1– 4 of general formula I are discussed. The data give further insight upon the potential NK-3 pharmacophore. In particular, it is highlighted that both the benzene-condensed ring and the quinoline nitrogen are crucial determinants for optimal binding affinity to the hNK-3 receptor. Some novel compounds maintained part of the binding affinity to the receptor ( 5, 6, 10 and 13) and compound 5, featuring the naphthalene ring system, appears to be suitable for further modifications; it offers the option to introduce electron-withdrawing groups at position 2 and 4, conferring on the ring an overall electron-deficiency similar to that of the quinoline.