Rational design of high affinity tachykinin NK1 receptor antagonists
| Autor: | Geoffery N. Woodruff, John O'Toole, John Hughes, David C. Rees, Michael Higginbottom, Steven Boyle, William Howson, David Christopher Horwell, Kevan Martin, Martyn Clive Pritchard, Steven Guard, Alexander T. McKnight, K.J. Watling, Edward Roberts, Jenny Raphy |
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| Rok vydání: | 1994 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy medicine.drug_class Guinea Pigs Urinary Bladder Clinical Biochemistry Pharmaceutical Science In Vitro Techniques Pharmacology Biochemistry Cell Line chemistry.chemical_compound Neurokinin-1 Receptor Antagonists Ileum In vivo Drug Discovery Radioligand medicine Animals Humans Receptor Molecular Biology Evans Blue Cerebral Cortex Molecular Structure Organic Chemistry Tryptophan Rational design Antagonist Blood Proteins Receptor antagonist Extravasation Kinetics chemistry Drug Design Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 2:357-370 |
| ISSN: | 0968-0896 |
| Popis: | The rational design of a non-peptide tachykinin NK 1 receptor antagonist, [(2-benzofuran)-CH 2 OCO]-( R )-α-MeTrp-( S )-NHCH(CH 3 )Ph ( 28 , PD 154075) is described. Compound 28 has a K i = 9 and 0.35 nM for the NK 1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [ 125 I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (K B = 0 3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID 50 of 0.02 mg kg −1 iv. |
| Databáze: | OpenAIRE |
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