Profiling two indole‐2‐carboxamides for allosteric modulation of the <scp>CB</scp>1 receptor

Ahn, Kyu‐Hong; Mahmoud, Mariam M.; Samala, Sushma; Lu, Dai; Kendall, Debra A.

doi:10.1111/jnc.12115

Cited by 29 publications

(77 citation statements)

References 12 publications

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“…These, and other allosteric modulators of the CB 1 receptor, have been characterized on the basis of their actions in radioligand-binding assays and other functional in vitro assays of CB 1 receptor signal transduction (Horswill et al, 2007;Navarro et al, 2009;Pamplona et al, 2012;Piscitelli et al, 2012;Ahn et al, 2013;Baillie et al, 2013). In vivo, the purported negative allosteric modulator, PSNCBAM-1, reduced food intake (Horswill et al, 2007), an action consistent with CB 1 orthosteric antagonism (Di Marzo et al, 2001), although CB 1 receptor mediation of this anorectic effect was not ascertained.…”

Section: Introductionmentioning

confidence: 99%

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

Ignatowska‐Jankowska

Baillie

Kinsey

et al. 2015

Neuropsychopharmacol

137

180

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The CB 1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ 9 -tetrahydrocannabinol and other CB 1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB 1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB 1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB 1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [ 3 H]CP55,940 to the CB 1 receptor as well as enhancing AEA-stimulated [35 S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB 1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB 1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB 1 PAM and provide the first proof of principle that CB 1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.

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Section: Introductionmentioning

confidence: 99%

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

Ignatowska‐Jankowska

Baillie

Kinsey

et al. 2015

Neuropsychopharmacol

137

180

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“…25 Subsequent work found that longer alkyl side chains with up to 9 carbon units at the C3 position of indole ring A could retain activity, whereas linkers other than an ethylene between the amide bond and the phenyl ring B resulted in total loss of activity. 26-28 In an attempt to expand our understanding of the structure-activity relationship on this scaffold, we have designed additional analogs by (i) exploring different substituents at the 4-, 3-, 2-positions of the phenyl ring B, (ii) examining several rigid cyclic ring linkers between the phenyl and the indole rings, and (iii) investigating the effects of shorter alkyl side chain at the C3 position and halogenations at the C5 position of the indole ring A. Here, we report the synthesis of these 1H-indole-2-carboxamide analogs and the evaluation of CB1 and CB2 activities in fluorometric imaging plate reader (FLIPR) based calcium mobilization assays.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators

Nguyễn

German

Decker

et al. 2015

Bioorganic & Medicinal Chemistry

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A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC50 value of 79 nM which is ~ 2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the Emax of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators.

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“…7–9 , Figure 2) reported previously [31–33]. Compounds 7 [31], 8 [33] and 9 [32, 35] have been demonstrated to have either comparable or improved allosteric effects to 1 [31–33]. Therefore, they were selected along with 1 as the parent compounds to introduce photoactivatable functionalities.…”

Section: Introductionmentioning

confidence: 98%

“…Thus, depending on the signaling pathways under investigation, compound 1 can behave either as a positive CB1 allosteric modulator [29] or a negative allosteric modulator [10, 30]. Following the discovery of 1 , several improved CB1 allosteric modulators have been identified from optimization of the indole-2-carboxamide scaffold [31–35]. However, the investigation of the precise location and the structure of their binding sites is still in its early stage [36–38].…”

Section: Introductionmentioning

confidence: 99%

“…To facilitate future proteomic study of allosteric sites on the CB1 receptor, we designed and synthesized several photoactivatable affinity ligands based on 1 and several other robust CB1 allosteric modulators (i.e. 7–9 , Figure 2) reported previously [31–33]. Compounds 7 [31], 8 [33] and 9 [32, 35] have been demonstrated to have either comparable or improved allosteric effects to 1 [31–33].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and biological evaluation of indole-2-carboxamides bearing photoactivatable functionalities as novel allosteric modulators for the cannabinoid CB1 receptor

Qiao

Ali

Ahn

et al. 2016

European Journal of Medicinal Chemistry

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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).

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Profiling two indole‐2‐carboxamides for allosteric modulation of the CB1 receptor

Cited by 29 publications

References 12 publications

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

Structure–activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators

Synthesis and biological evaluation of indole-2-carboxamides bearing photoactivatable functionalities as novel allosteric modulators for the cannabinoid CB1 receptor

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