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

Autor: Blaazer AR; Chemical Design & Synthesis Unit, Abbott Healthcare Products B.V., C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. ton@blaazer.nl, Lange JH, van der Neut MA, Mulder A, den Boon FS, Werkman TR, Kruse CG, Wadman WJ
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2011 Oct; Vol. 46 (10), pp. 5086-98. Date of Electronic Publication: 2011 Aug 23.
DOI: 10.1016/j.ejmech.2011.08.021
Abstrakt: 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.
(Copyright © 2011 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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