Exploring the Benzimidazole Ring as a Substitution for Indole in Cannabinoid Allosteric Modulators

Hernandez-FolgadoLaura,; StevensonLesley, A; MoralesPaula,; Gómez-CañasMaría,; Ruth, PazosMaría; Grazia, CascioMaria; Jagerovic, Nadine; ElgueroJosé,; PertweeRoger,; GoyaPilar,

doi:10.1089/can.2016.0003

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…(2) The indole ring is critical. The replacement of this ring with other heteroaromatic rings, such as benzofuran or benzimidazole, abolishes or reduces the allosteric activity [72,77]. 3The length of the linker between the amide group and the aminophenyl ring is instrumental.…”

Section: Sars Of Indole-2-carboxamides Represented By Org27569mentioning

confidence: 99%

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Immadi

et al. 2018

Acta Pharmacol Sin

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The cannabinoid type-1 (CB 1) receptor, a G-protein-coupled receptor, is an attractive target for drug discovery due to its involvement in many physiological processes. Historically, drug discovery efforts targeting the CB 1 receptor have focused on the development of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind. Research performed over the last several decades has revealed substantial difficulties in translating CB 1 orthosteric ligands into druggable candidates. The difficulty is mainly due to the adverse effects associated with orthosteric CB 1 ligands. Recent discoveries of allosteric CB 1 modulators provide tremendous opportunities to develop CB 1 ligands with novel mechanisms of action; these ligands may potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB 1 receptor. In this paper, we review and summarize the complex pharmacological profiles of each class of CB 1 allosteric modulators, the development of new classes of CB 1 allosteric modulators and the results from in vivo assessments of their therapeutic value.

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Section: Sars Of Indole-2-carboxamides Represented By Org27569mentioning

confidence: 99%

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Immadi

et al. 2018

Acta Pharmacol Sin

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“… 9 Similarly, the binding affinities of benzimidazole analogs of Org27569 were abolished, while allosteric modulation on agonist-induced GTPγS binding was maintained. 10 …”

Section: Introductionmentioning

confidence: 99%

Exploring 6-Azaindole and 7-Azaindole Rings for Developing Cannabinoid Receptor 1 Allosteric Modulators

Immadi

Dopart

et al. 2018

Cannabis and Cannabinoid Research

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Introduction and Objective: Org27569 is a prototypical allosteric modulator of the cannabinoid receptor 1 (CB1). It belongs to the indole-2-carboxamide scaffold and has been intensively investigated in pharmacology and in structure–activity relationship (SAR) studies. Although azaindoles are rare in natural products and differ only by the presence of an extra ring nitrogen, they were demonstrated as valuable bioisosteres in many pharmacologically important molecules. To extend the SAR investigation of the indole-2-carboxamide class of CB1 allosteric modulators, azaindole (pyrrolopyridine) rings were used to replace the indole ring of Org27569 analogs to explore the potential of azaindole-2-carboxamides as CB1 allosteric modulators. Using 6- and 7-azaindole in lieu of the indole moiety within this class of CB1 allosteric modulators indeed improved the aqueous solubility.Materials and Methods: We synthesized 6- and 7-azaindole-2-carboxamides and their indole-2-carboxamide counterparts. The molecules were evaluated by [3H]CP55,940 binding and [35S]GTPγS binding assays for their allosteric modulation of the CB1 receptor.Results: The 7-azaindole-2-carboxamides lost the ability to bind to the CB1 receptor. The 6-azaindole-2-carboxamides (e.g., 3c and 3d) showed markedly reduced binding affinities to the CB1 receptor in comparison with their indole-2-carboxamide counterparts. However, they behaved similarly as indole-2-carboxamides in potentiating the orthosteric agonist binding and inhibiting the orthosteric agonist-induced G-protein coupling. The results indicated that some azaindole scaffolds (e.g., 6-azaindole) are worth further exploration, whereas the 7-azaindole ring is not a viable bioisostere of the indole ring in the Org27569 class of CB1 allosteric modulators.

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Theoretical and Spectroscopic Characterization of API-Related Azoles in Solution and in Solid State

Marín‐Luna

Claramunt

Elguero

et al. 2020

CPD

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: Azoles are a family of five-membered azacyclic compounds with relevant biological and pharmacological activity. Different subclasses of azoles are defined depending on the atomic arrangement and the number of nitrogen atoms present in the ring: pyrazoles, indazoles, imidazoles, benzimidazoles, triazoles, benzotriazoles, tetrazoles and pentazoles. The complete characterization of their structure and the knowledge about their crystal packing and physical and chemical properties are of vital importance to advance in the design of new azole-containing drugs. In this review, we report the latest recent contributions to azole chemistry, in particular, those in which theoretical studies have been performed.

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Exploring the Benzimidazole Ring as a Substitution for Indole in Cannabinoid Allosteric Modulators

Cited by 3 publications

References 17 publications

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Exploring 6-Azaindole and 7-Azaindole Rings for Developing Cannabinoid Receptor 1 Allosteric Modulators

Theoretical and Spectroscopic Characterization of API-Related Azoles in Solution and in Solid State

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