Chang-Jiang Qiao1, Hamed I Ali2, Kwang H Ahn3, Srikanth Kolluru2, Debra A Kendall4, Dai Lu5. 1. 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. 2. Irma Lerma Rangel College of Pharmacy, Health Science Center, Texas A&M University, 1010 West Avenue B, Kingsville, TX 78363, United States. 3. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States. 4. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States. Electronic address: debra.kendall@uconn.edu. 5. 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.
Abstract
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).
5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569, 1) is a prototypical allosteric mon class="Chemical">dulator for the cannabinoidCB1 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 andphenyltrifluoromethyldiazrine. 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).
Authors: J G Horswill; U Bali; S Shaaban; J F Keily; P Jeevaratnam; A J Babbs; C Reynet; P Wong Kai In Journal: Br J Pharmacol Date: 2007-06-25 Impact factor: 8.739
Authors: Fabricio A Pamplona; Juliano Ferreira; Octávio Menezes de Lima; Filipe Silveira Duarte; Allisson Freire Bento; Stefânia Forner; Jardel G Villarinho; Luigi Bellocchio; Luigi Bellochio; Carsten T Wotjak; Raissa Lerner; Krisztina Monory; Beat Lutz; Claudio Canetti; Isabelle Matias; João Batista Calixto; Giovanni Marsicano; Marilia Z P Guimarães; Reinaldo N Takahashi Journal: Proc Natl Acad Sci U S A Date: 2012-11-12 Impact factor: 11.205
Authors: Thuy Nguyen; Jun-Xu Li; Brian F Thomas; Jenny L Wiley; Terry P Kenakin; Yanan Zhang Journal: Med Res Rev Date: 2016-11-23 Impact factor: 12.944
Authors: Samuel D Banister; Kaavya Krishna Kumar; Vineet Kumar; Brian K Kobilka; Sanjay V Malhotra Journal: Medchemcomm Date: 2019-03-18 Impact factor: 3.597