Synthesis and biological evaluation of indole-2-carboxamides bearing photoactivatable functionalities as novel allosteric modulators for the cannabinoid CB1 receptor.
5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569, 1) is a prototypical allosteric modulator for the cannabinoid CB1 receptor. Based on this indole-2-carboxamide scaffold, we designed and synthesized novel CB1 allosteric modulators that possess photoactivatable functionalities, which include benzophenone, phenyl azide, aliphatic azide and phenyltrifluoromethyldiazrine. To assess their allosteric effects, the dissociation constant (KB) and allosteric binding cooperativity factor (α) were determined and compared to their parent compounds. Within this series, benzophenone-containing compounds 26 and 27, phenylazide-containing compound 28, and the aliphatic azide containing compound 36b showed allosteric binding parameters (KB and α) comparable to their parent compound 1, 7, 8, and 9, respectively. We further assessed these modulators for their impact on G-protein coupling activity. Interestingly, these compounds exhibited negative allosteric modulator properties in a manner similar to their parent compounds, which antagonize agonist-induced G-protein coupling. These novel CB1 allosteric modulators, possessing photoactivatable functionalities, provide valuable tools for future photo-affinity labeling and mapping the CB1 allosteric binding site(s).
Irma Lerma Rangel College of Pharmacy, Health Science Center, Texas A&M University, 1010 West Avenue B, Kingsville, TX 78363, United States; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Chang-Jiang
CJ
Qiao
Irma Lerma Rangel College of Pharmacy, Health Science Center, Texas A&M University, 1010 West Avenue B, Kingsville, TX 78363, United States.
Hamed I
HI
Ali
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States.
Kwang H
KH
Ahn
Irma Lerma Rangel College of Pharmacy, Health Science Center, Texas A&M University, 1010 West Avenue B, Kingsville, TX 78363, United States.
Srikanth
S
Kolluru
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States. Electronic address: debra.kendall@uconn.edu.
Debra A
DA
Kendall
Irma Lerma Rangel College of Pharmacy, Health Science Center, Texas A&M University, 1010 West Avenue B, Kingsville, TX 78363, United States. Electronic address: dlu@tamhsc.edu.
Dai
D
Lu
D000494:Allosteric Regulation / Q000187:drug effects / Q000528:radiation effects; D060326:Chemistry Techniques, Synthetic; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008027:Light; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry / Q000378:metabolism*
D007211:Indoles; D043884:Receptor, Cannabinoid, CB1
Allosteric modulator; Cannabinoid receptor; Photoactivatable ligands; Photoaffinity labeling