ArticleJournal of medicinal chemistry2014
Optimization of chemical functionalities of indole-2-carboxamides to improve allosteric parameters for the cannabinoid receptor 1 (CB1).
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 53 citations in OpenAlex.
- Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case Study of Cannabinoid CB1 Receptor Bound to a Negative Allosteric Modulator, ORG27569, and Analogs.Journal of medicinal chemistry · 2022Article
- In vivo evaluation of the CBPharmacology, biochemistry, and behavior · 2020Article
- Selective modulation of the cannabinoid type 1 (CBMedChemComm · 2019Review
- Translational potential of allosteric modulators targeting the cannabinoid CBActa pharmacologica Sinica · 2019Review
- Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.Journal of medicinal chemistry · 2019Review
- New Insights in Cannabinoid Receptor Structure and Signaling.Current molecular pharmacology · 2019Review
- Overcoming the Psychiatric Side Effects of the Cannabinoid CB1 Receptor Antagonists: Current Approaches for Therapeutics Development.Current topics in medicinal chemistry · 2019Review
- Allosteric modulators of cannabinoid receptor 1: developing compounds for improved specificity.Drug metabolism reviews · 2018Review
- Exploring 6-Azaindole and 7-Azaindole Rings for Developing Cannabinoid Receptor 1 Allosteric Modulators.Cannabis and cannabinoid research · 2018Article
- Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities.Neuropharmacology · 2017Review
- Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor.Medicinal research reviews · 2017Review
- Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CBJournal of medicinal chemistry · 2017Article
- Assessing Allosteric Modulation of CBMethods in enzymology · 2017Article
- Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target.Expert opinion on drug discovery · 2016Review
- Synthesis and biological evaluation of indole-2-carboxamides bearing photoactivatable functionalities as novel allosteric modulators for the cannabinoid CB1 receptor.European journal of medicinal chemistry · 2016Article
- Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s).Journal of medicinal chemistry · 2016Article
- Allosteric Modulators of the CBCannabis and cannabinoid research · 2016Review
- Minireview: From the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation.Molecular endocrinology (Baltimore, Md.) · 2015Review
- Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators.Bioorganic & medicinal chemistry · 2015Article
- Diarylureas as allosteric modulators of the cannabinoid CB1 receptor: structure-activity relationship studies on 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1).Journal of medicinal chemistry · 2014Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (1; ORG27569) is a prototypical allosteric modulator for the cannabinoid type 1 receptor (CB1). Here, we reveal key structural requirements of indole-2-carboxamides for allosteric modulation of CB1: a critical chain length at the C3-position, an electron withdrawing group at the C5-position, the length of the linker between the amide bond and the phenyl ring B, and the amino substituent on the phenyl ring B. These significantly impact the binding affinity (KB) and the binding cooperativity (α). A potent CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-propyl-1H-indole-2-carboxamide (12d) was identified. It exhibited a KB of 259.3 nM with a strikingly high binding α of 24.5. We also identified 5-chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-indole-2-carboxamide (12f) with a KB of 89.1 nM, which is among the lowest KB values obtained for any allosteric modulator of CB1. These positive allosteric modulators of orthosteric agonist binding nonetheless antagonized the agonist-induced G-protein coupling to the CB1 receptor, yet induced β-arrestin mediated ERK1/2 phosphorylation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.