Indole-2-carboxamides

Indole-2-Carboxamides;

Abstract

 

 

 

The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor.

 

 

5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569; 1) represents a new class of indole-2-carboxamides that exhibit allostery of CB1.

 

 

To better understand the SAR, a group of indole-2-carboxamide analogues were synthesized and assessed for allostery of the CB1 receptor.

 

We found that within the structure of indole-2-carboxamides, the presence of the indole ring is preferred for maintaining the modulator’s high binding affinity for the allosteric site but not for generating allostery on the orthosteric site.

 

However, the C3 substituents of the indole-2-carboxamides significantly impact the allostery of the ligand.

 

 

A robust CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-pentyl-1H-indole-2-carboxamide (11j) was identified.

 

It showed an equilibrium dissociation constant (K_B) of 167.3 nM with a markedly high binding cooperativity factor (α = 16.55) and potent antagonism of agonist-induced GTPγS binding.

 

 

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This article has been cited by 2 ACS Journal articles (2 most recent appear below).

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  Palladium-Catalyzed Tandem Intramolecular Oxy/Amino-Palladation/Isocyanide Insertion: Synthesis of α-Benzofuranyl/Indolylacetamides

  Nuligonda Thirupathi, Madala Hari Babu, Vikas Dwivedi, Ruchir Kant, and Maddi Sridhar Reddy
  Organic Letters2014 16 (11), 2908-2911

  • Palladium-Catalyzed Tandem Intramolecular Oxy/Amino-Palladation/Isocyanide Insertion: Synthesis of α-Benzofuranyl/Indolylacetamides

    NuligondaThirupathi, MadalaHari Babu, VikasDwivedi, RuchirKant, and MaddiSridhar Reddy
    Organic Letters2014 16 (11), 2908-2911
    A novel palladium-catalyzed approach to 2-benzofuranyl/indolylacetamides from 1-(o-hydroxy/aminophenyl)propargylic alcohols and isocyanides is described. The reaction proceeds through a cascade that includes oxy/aminopalladation, isocyanide insertion, and ...
    
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  Optimization of Chemical Functionalities of Indole-2-carboxamides To Improve Allosteric Parameters for the Cannabinoid Receptor 1 (CB1)

  Leepakshi Khurana, Hamed I. Ali, Teresa Olszewska, Kwang H. Ahn, Aparna Damaraju, Debra A. Kendall, and Dai Lu
  Journal of Medicinal Chemistry2014 57 (7), 3040-3052