Back to Search
Start Over
Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity
- Source :
- Journal of Medicinal Chemistry, 46, 5086-5098. American Chemical Society
- Publication Year :
- 2011
- Publisher :
- American Chemical Society, 2011.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00222623
- Volume :
- 46
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....e9add9a1145563982df9aced0b673e8c