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Novel γ-Butyrolactone Derivatives as Muscarinic Receptor Antagonists: Pharmacophore Elucidation and Docking Analyses

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Crystallizing Ideas – The Role of Chemistry

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Abstract

Our efforts in design and development of novel muscarinic acetylcholine receptor (mAChR) antagonists led to the development of a novel series of γ-butyrolactone derivatives. We were interested in understanding the contributions of the structural features of these molecules for receptor affinity and subtype selectivity, if any, to guide further design of second-generation analogs with tailor-made potency and selectivity. Initially, 3D pharmacophore hypotheses were developed using high affinity M1 and M2 antagonist ligands. The ‘extended’ and ‘compact’ hypotheses were then used for the retrospective virtual screening of the γ-butyrolactone derivatives. Further, these molecules were then docked into the M2 receptor orthosteric binding site. The results obtained from the pharmacophore- and structure-based investigations were in agreement with the structure–activity relationship (SAR) observations. The key findings of these studies will be helpful for further design and development of subtype-selective muscarinic receptor ligands.

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Acknowledgements

RB and PK thank Dr. R.S. Gaud, Dean, SPP School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai, India, for his constant support and encouragement during preparation of this book chapter.

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Authors and Affiliations

  1. SPP School of Pharmacy and Technology Management, SVKM’s NMIMS, V.L. Mehta Road, Vile Parle (West), Mumbai, 400056, India

    Richie R. Bhandare & Prashant S. Kharkar

  2. Department of Pharmaceutical Sciences, School of Pharmacy, Moulder Center for Drug Discovery Research, Temple University, 3307 N. Broad Street, Philadelphia, PA, 19140, USA

    Richie R. Bhandare, Rong Gao & Daniel J. Canney

Authors
  1. Richie R. Bhandare
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  2. Rong Gao
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  3. Daniel J. Canney
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  4. Prashant S. Kharkar
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Corresponding author

Correspondence to Prashant S. Kharkar .

Editor information

Editors and Affiliations

  1. Dep. of Chemistry, Fac. of Science, University of Mauritius, Reduit, Mauritius

    Ponnadurai Ramasami

  2. Dept of Chemistry, Faculty of Scien, University of Mauritius, Reduit, Mauritius

    Minu Gupta Bhowon

  3. Dept. of Chemistry, Faculty of Scie, University of Mauritius, Reduit, Mauritius

    Sabina Jhaumeer Laulloo

  4. Reduit, Mauritius

    Henri Li Kam Wah

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Bhandare, R.R., Gao, R., Canney, D.J., Kharkar, P.S. (2016). Novel γ-Butyrolactone Derivatives as Muscarinic Receptor Antagonists: Pharmacophore Elucidation and Docking Analyses. In: Ramasami, P., Gupta Bhowon, M., Jhaumeer Laulloo, S., Li Kam Wah, H. (eds) Crystallizing Ideas – The Role of Chemistry. Springer, Cham. https://doi.org/10.1007/978-3-319-31759-5_11

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