Structure–Activity Relationships of 1‐Benzoylazulenes at the OX₁ and OX₂ Orexin Receptors

Abstract

and carboxyl or ester groups at the 6-position,w hile af ew compounds with only one of these features were inactive (as an example compound 3 in Figure2). We therefore synthe-sized and tested 21 new 1,6-disubstituted azulenes. At the 1position, we aimed to modify the benzoyl group either by polar substitutionso rb yr eplacing it with other aromatic Figure 2. A) Screeningo fC a 2 + responses of all 21 azulene-based and six indole-basedc ompounds at 10 mm.Azulene derivativesa re presenteda sh ollow diamondsa nd indole derivatives as filled circles. B) Structureso fc ompounds 15, 26,and 28 that displayed the highest Ca 2 + responses in the screening, and previouslydisclosedc ompounds 1, 3, 37,and 40.[12] C)-F) To tal and orexin-receptor-specific Ca 2 + responses of 1 (C, 10 mm data from ref.[12]), 26 (D), 28 (E), and 37 (F). Ca 2 + responses areg iven as apercentage of the maximal response (E max )o forexin-A. The responses wereseparately normalized to the E max of orexin-A for each independent experiment beforeaveraging; n = 3-6.Scheme1.Synthesis of compounds 5-36:a)appropriate N,N-dimethylbenzamide, POCl 3 ,1,4-dioxane, mw,100 8C, 4-5 h, 22 %( 5), 18 %( 6), 44 %( 7), 31 %(8), 29 %( 9), 0% (11); b) 1) 2-chloro-N,N-diethylacetamide, POCl 3 ,1,4-dioxane, mw,1 00 8C, 2h,33%,2 )thioacetamide,E tOH, mw,1 20 8C, 30 min,7 1%;c )1)oxalyl chloride,t oluene, RT,1h, 2) appropriate amine, CH 2 Cl 2 ,10-30 min, 64 %( 14), 50 %( 15); d) 1) phosgene, toluene, 80 8C, overnight, 2) appropriate amine, 0 8C, 15-30 min, 35 %( 16), 9% (17), 49 %( 18), 84 %(19); e) 1) EDC·HCl,H OBt·H 2 O, DMF,08C, 15 min, RT,1h, 2) appropriate amined erivative, RT,1 -2.5 h, 79 %( 21), 85 %( 22), 88 %( 23), 49 %(24), 81 %( 25), 80 %( 26), 87 %( 28); f) NaOH, THF,MeOH,H 2 O, RT,30min, 98 %; g) benzoyl chloride, Et 3 N, CH 2 Cl 2 ,R T, 23 h, 59 %( 31), 22 %( 32); h) N,N-dimethylbenzamide, POCl 3 ,m w, 100 8C, 1-3 h, 2% (33), 3% (34), 23 %( 35), 48 %( 36).

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

“…Interestingly, in this campaign, it was clear that subtle changes in substituents had massive impacts on whether the compound had weak partial agonism or potentiating effects. 111 Azulene-based compounds 67 and 68 emerged as weak dual OX-R agonists, showing dose-dependent OX-R activation and similar magnitude to the previously reported compound 62 (Figure 30). 109 Additionally the previously reported compound 69 109 showed the highest pecentage of the E max of orexin-A in both receptor subtypes (approximately 18%), but it only elicited those responses at the very high concentration of 45 μM (Figure 30).…”

“…The authors summarized that to achieve agonism and Ca 2+ signaling potentiation at the OX1‐R, hydrogen‐bond acceptor groups at positions 1 (i.e., benzoyl) and 6 (carboxylic groups) are important, whereas at position 3 H‐bonding is not necessary, but is well tolerated. Interestingly, in this campaign, it was clear that subtle changes in substituents had massive impacts on whether the compound had weak partial agonism or potentiating effects 111 . Azulene‐based compounds 67 and 68 emerged as weak dual OX‐R agonists, showing dose‐dependent OX‐R activation and similar magnitude to the previously reported compound 62 (Figure 30).…”

“…Replacing the azulene ring with substituted indoles did not alter the pharmacological profiles of the analogs, as long as the substitutions remained in similar spatial locations and chemical spaces. Compounds 70-72 (Figure 30) behaved as preferential OX1-R potentiators, with some non-orexin nonspecific effects observed at OX2-R. 111 This ultimately demonstrates that other heteroaromatic pharmacophores should be further studied to synthesize potentiator/allosteric modulators for OX-R, to build upon these studies and achieve a more sustainable subtype-selectivity and more translational tools.…”

In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine

“…Turku et al used in silico analytic software to propose compounds for synthesis of orexin (hypocretin) OX1 and OX2 receptor ligands [63]. As the receptor is involved in the sleep-wake regulation, the antagonists are considered to treat insomnia.…”

Orexin Signaling: A Complex, Multifaceted Process

“…This is in part due to evidence indicating that stimulation of OX 1 R in the ventral tegmental area increases dopaminergic transmission, raising concerns that OX 1 R-targeted agonists may result in dependency issues ( Nakamura et al, 2000 ; Yukitake et al, 2019 ). For the agonists that have been developed ( Nagahara et al, 2015 ; Turku et al, 2016 , 2019 ; Leino et al, 2018 ; Rinne et al, 2018 ), comprehensive analysis of their pharmacological profiles has not been conducted. Studies have mainly relied upon Ca 2+ measurements to determine receptor selectivity and agonist activity, since until recently, FLIPR has been a traditional workhorse for drug screening in industry.…”