A new synthetic approach of N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide (JTC-801) and its analogues and their pharmacological evaluation as nociceptin receptor (NOP) antagonists

A series of 4-amino-2-methylquinoline and 4-aminoquinazoline derivatives, including the reference NOP antagonist JTC-801, were synthesized by an alternative pathway and their in vitro pharmacological properties were investigated. 3-Substitution of the quinoline ring resulted very critical for affini...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2004-12, Vol.39 (12), p.1047-1057
Main Authors: Sestili, Isabella, Borioni, Anna, Mustazza, Carlo, Rodomonte, Andrea, Turchetto, Luciana, Sbraccia, Maria, Riitano, Daniela, Del Giudice, Maria Rosaria
Format: Article
Language:English
Subjects:
Aminoquinolines - chemical synthesis
Aminoquinolines - chemistry
Aminoquinolines - metabolism
Aminoquinolines - pharmacology
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - metabolism
Benzamides - pharmacology
Benzamidoquinazolines
Benzamidoquinolines
Binding, Competitive
Biological and medical sciences
Calorimetry
Dose-Response Relationship, Drug
GTP-Binding Proteins - metabolism
Guanosine 5'-O-(3-Thiotriphosphate) - metabolism
Humans
In Vitro Techniques
Logistic Models
Medical sciences
Miscellaneous
Molecular Conformation
Molecular Structure
Narcotic Antagonists
Nociceptin
Nociceptin Receptor
NOP receptor antagonists
Opioid Peptides - metabolism
Opioids
Pharmacology. Drug treatments
Protein Binding
Receptors, Opioid - metabolism
Structure-Activity Relationship
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Description
Summary:A series of 4-amino-2-methylquinoline and 4-aminoquinazoline derivatives, including the reference NOP antagonist JTC-801, were synthesized by an alternative pathway and their in vitro pharmacological properties were investigated. 3-Substitution of the quinoline ring resulted very critical for affinity. So 3-methyl derivative 4j showed a similar potency compared with the reference 4h while bulky lipophilic or electron withdrawing groups in the same position strongly decreased affinity. Structural and conformational requirements for affinity were outlined by NOE NMR and computational methods and suggestions for a pharmacophore model design were provided.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2004.09.009