Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic action
| Autor: | Shuji Saito, Yoshihisa Toda, Tomoko Ishizaka, Tomomi Yamaguchi, Hiroshi Ohta, Izumi Iida, Mitsukane Yoshinaga, Nobuko Futaki, Makoto Tatsuzuki, Yasumitsu Tomishima |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Agonist Cannabinoid receptor Stereochemistry medicine.drug_class Clinical Biochemistry Imine Pharmaceutical Science Biochemistry Chemical synthesis Rats Sprague-Dawley Receptor Cannabinoid CB2 Structure-Activity Relationship chemistry.chemical_compound Oral administration Drug Discovery medicine Cannabinoid receptor type 2 Animals Humans Molecular Biology IC50 Molecular Structure Chemistry Organic Chemistry Cannabinoid Receptor Agonists Rats Pyrazoles Molecular Medicine lipids (amino acids peptides and proteins) Imines |
| Zdroj: | Bioorganic & Medicinal Chemistry. 16:1111-1124 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2007.10.087 |
| Popis: | In this study, a novel series of CB(2) receptor agonist imine derivatives, 1-6, was synthesized and evaluated for activity against the CB(2) receptor. In a previous paper we reported the synthesis and SARs of thiazole derivative 1, a potent CB(2) receptor agonist, but we had not assessed chemical modifications of the 5-membered heteroring of 1. In the present study, we therefore tried chemically modifying the 5-membered heteroring of 1 in an attempt to further improve binding affinity for the CB(2) receptor. In the course of making the structural modifications, we discovered that a novel pyrazole derivative 6b (CBS0550) had high affinity for the CB(2) receptor (IC(50)=2.9 nM, EC(50)=1.8 nM, E(max)=85%), high selectivity for CB(2) (CB(1) IC(50)/CB(2) IC(50)=1400), and good physicochemical properties (solubility in water: 5.9 mg/100mL at 25 degrees C). Oral administration of 6b to rats at a dose of 10mg/kg resulted in significant plasma concentrations, and orally administered compound 6b significantly reversed mechanical hyperalgesia in the Randall-Selitto model of inflammatory pain in rats. |
| Databáze: | OpenAIRE |
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