Synthesis, modelling and NK1 antagonist evaluation of a non-rigid cyclopropane-containing analogue of CP-99,994

• Published in: Bioorganic & medicinal chemistry letters Vol. 11; no. 5; pp. 659 - 661
• Main Authors: AITKEN, David J, ONGERI, Sandrine, VALLEE-GOYET, Danielle, GRAMAIN, Jean-Claude, HUSSON, Henri-Philippe
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 12.03.2001
• Subjects: Biological and medical sciences; Computer Simulation; Medical sciences; Models, Chemical; Models, Molecular; Molecular Conformation; Molecular Structure; Neurokinin-1 Receptor Antagonists; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Receptors, Neurokinin-1 - chemistry; Receptors, Neurokinin-1 - metabolism; Stereoisomerism; Diamine; Molecular flexibility; Cyclopropane derivatives; NK1 Tachykinin receptor; Ether; Molecular model; Benzenic compound; Antagonist; Chemical synthesis; Modeling; Biological activity; Conformation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00020-8

A non-rigid cyclopropane-containing diamine analogue of CP-99,994 was synthesised and was found to have only moderate NK1 receptor binding affinity. Molecular dynamics calculations of the conformational space of the former compound gave good correlation between observed activity and a recently published pharmacophore model, lending predictive value to the latter.