Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity
| Autor: | Taco R. Werkman, Wytse J. Wadman, A.R. Blaazer, Femke S. den Boon, Chris G. Kruse, Josephus H. M. Lange, Martina A.W. van der Neut, Arie H. Mulder |
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| Přispěvatelé: | Cellular and Computational Neuroscience (SILS, FNWI) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Cannabinoid receptor Indoles medicine.drug_class Stereochemistry medicine.medical_treatment Carboxamide CHO Cells Ligands Receptor Cannabinoid CB2 chemistry.chemical_compound Structure-Activity Relationship Cricetinae Drug Discovery medicine Cannabinoid receptor type 2 Animals Humans Rats Wistar Receptors Cannabinoid Pharmacology Indole test Cannabinoid Receptor Agonists Chemistry Organic Chemistry Brain Biological activity General Medicine Rats lipids (amino acids peptides and proteins) Bioisostere Cannabinoid |
| Zdroj: | Journal of Medicinal Chemistry, 46, 5086-5098. American Chemical Society |
| ISSN: | 0022-2623 |
| Popis: | The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB(1)/CB(2) dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ~80 fold selectivity for CB(1) over the CB(2) receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission. |
| Databáze: | OpenAIRE |
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