title: Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity.
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.
authors: Chemical Design & Synthesis Unit, Abbott Healthcare Products B.V., C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. ton@blaazer.nl
authors: Antoni R
authors: AR
authors: Blaazer
authors: Jos H M
authors: JH
authors: Lange
authors: Martina A W
authors: MA
authors: van der Neut
authors: Arie
authors: A
authors: Mulder
authors: Femke S
authors: FS
authors: den Boon
authors: Taco R
authors: TR
authors: Werkman
authors: Chris G
authors: CG
authors: Kruse
authors: Wytse J
authors: WJ
authors: Wadman
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D063386:Cannabinoid Receptor Agonists; D006224:Cricetinae; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D063386:Cannabinoid Receptor Agonists; D007211:Indoles; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid