Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure–activity relationships, physicochemical properties and biological activity

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) 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 CB1/CB2 dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ∼80 fold selectivity for CB1 over the CB2 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.

The structure-activity relationships and physicochemical properties of a novel series of indole-related cannabinoid receptor ligands are reported. Potent cannabinoid receptor agonists with improved physicochemical properties have been discovered among indoles 11–20 and azaindoles 21–25.Figure optionsDownload as PowerPoint slideHighlights
► Novel series of potent indole-based cannabinoid CB1/CB2 receptor ligands were designed.
► Active azaindoles (pyrrolopyridines) elicited favorable physicochemical properties.
► A potent indole-3-carboxamide with ∼80-fold CB1 receptor subtype selectivity was identified.
► Compounds potently modulated excitatory synaptic transmission in rat brain slices.