Discovery of a Novel Class of Selective Non-Peptide Antagonists for the Human Neurokinin-3 Receptor. 1. Identification of the 4-Quinolinecarboxamide Framework
| Autor: | Douglas W. P. Hay, Vittorio Vecchietti, Carlo Farina, Mark A. Luttmann, Henry M. Sarau, Roberto Rigolio, Andrew D. Medhurst, Luca F. Raveglia, Dulcie B. Schmidt, Giuseppe Giardina, Mario Grugni |
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| Rok vydání: | 1997 |
| Předmět: |
animal structures
Chemical Phenomena Stereochemistry CHO Cells Substance P Binding Competitive Chemical synthesis Structure-Activity Relationship Cricetinae Drug Discovery Animals Humans Receptor Molecular Structure Bicyclic molecule Chemistry Physical Chemistry Chinese hamster ovary cell Antagonist Hydrogen Bonding Receptors Neurokinin-3 Stereoisomerism Peptide Fragments Recombinant Proteins In vitro Biochemistry embryonic structures Quinolines Molecular Medicine Rabbits Selectivity Neurokinin 3 receptor Muscle Contraction |
| Zdroj: | Journal of Medicinal Chemistry. 40:1794-1807 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm960818o |
| Popis: | A novel class of potent and selective non-peptide neurokinin-3 (NK-3) receptor antagonists, featuring the 4-quinolinecarboxamide framework, has been designed based upon chemically diverse NK-1 receptor antagonists. The novel compounds 33-76, prompted by chemical modifications of the prototype 4, have been characterized by binding analysis using a membrane preparation of chinese hamster ovary (CHO) cells expressing the human neurokinin-3 receptors (hNK-3-CHO), and clear structure-activity relationships (SARs) have been established. From SARs, (R)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (65, SB 218795, hNK-3-CHO binding Ki = 13 nM) emerged as one of the most potent compounds of this novel class. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 65 is about 90-fold selective for hNK-3 versus hNK-2 receptors (hNK-2-CHO binding Ki = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding Ki =100 microM). In vitro functional studies in rabbit isolated iris sphincter muscle preparation demonstrated that 65 is a competitive antagonist of the contractile response induced by the potent and selective NK-3 receptor agonist senktide with a Kb = 43 nM. Overall, the data indicate that 65 is a potent and selective hNK-3 receptor antagonist and a useful lead for further chemical optimization. |
| Databáze: | OpenAIRE |
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