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CoMFA and CoMSIA analyses on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole derivatives as selective CB2 receptor agonists

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Abstract

Novel classes of cannabinoid 2 receptor (CB2) agonists based on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over cannabinoid 1 receptor (CB1). A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, initially on each series of agonists, and subsequently on all compounds together, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing cross-validated r2 (rcv 2) = 0.680, non cross-validated r2 (rncv 2) = 0.97 and test set \( {{\hbox{r}}^2}\left( {{\hbox{r}}_{\rm{pred}}^2} \right) = 0.{93} \). The study provides useful suggestions for the design of new analogues with improved affinity.

Contour maps of model C CoMSIA hydrophobic (yellow, favoured; white, disfavoured) and CoMSIA H-bond acceptor (magenta, favoured; green, disfavoured) regions are displayed around compound 8 (orange), and 31 (green). Ligands are depicted in stick mode

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Acknowledgments

This work was supported by University of Genova. Progetto Ateneo 2007. Fondazione Carige is gratefully acknowledged for financially supporting E.C. and S.C.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV n.3, 16132, Genova, Italy

    Elena Cichero, Sara Cesarini, Luisa Mosti & Paola Fossa

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  1. Elena Cichero
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  2. Sara Cesarini
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  3. Luisa Mosti
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  4. Paola Fossa
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Correspondence to Elena Cichero.

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Cichero, E., Cesarini, S., Mosti, L. et al. CoMFA and CoMSIA analyses on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole derivatives as selective CB2 receptor agonists. J Mol Model 16, 1481–1498 (2010). https://doi.org/10.1007/s00894-010-0664-1

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  • DOI: https://doi.org/10.1007/s00894-010-0664-1

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