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Advances in Structure–Activity Relationship Studies on Potassium Channel Modulators

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Ion Channels and Their Inhibitors

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Abstract

Ion channels are part of cell membranes. They control the influx and efflux of ions such as sodium, potassium, calcium, or chloride, as well as ligands of several biochemical processes. Due to this, they play important role in a variety of diseases ranging from the cardiovascular, nervous, immune and endocrine systems to the cancer metastasis. Moreover, a number of chemicals and genetic disorders disrupt functioning of ion channels, which in turn can lead to aggrieved situations. This makes ion channels as potential targets in drug discovery programs. However, because of ion channels’ ubiquitous nature and high variability even within a given family, identification of drugs acting via them with specificity and high therapeutic value is a challenge! With a brief introduction to the fundamental aspects of ion channels, the review chapter explored the structure-activity advancements made on some potassium channel modulators namely, benzodiazepines, cromakalim analogues, benzothiadiazines, khellinone derivatives and other related chemical prototypes. Also, attempts were made to analyze the scope of these and other ion channel modulators in addressing the challenges faced in the chemotherapy of various diseases.

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Abbreviations

3D-MoRSE:

3D Molecule representation of structures based on electron diffraction

ABC:

ATP-binding cassette

ADMET:

Absorption, distribution, metabolism, elimination and toxicity

ATP:

Adenosine triphosphate

BK-channels:

Big K+-channels

CFTR:

Cystic fibrosis transmembrane conductance regulator

CODESSA:

Comprehensive descriptors for structural and statistical analysis

CoMSIA:

Comparative molecular similarity analysis

CP-MLR:

Combinatorial protocol in multiple linear regression

EC50 :

Half maximal effective concentration

G/PLS:

Genetic partial least squares

GFA:

Genetic function approximation

GRIND:

Grid-independent descriptors

hERG:

Human ether-à-go-go-related gene

HOMO:

Highest occupied molecular orbital

IC50 :

Half maximal inhibitory concentration

I K :

Cardiac rectifier potassium ion current

I Kr :

Rapidly activating ion current

I Ks :

Slowly activating ion current

KATP:

ATP-sensitive K+-channel

K ir/IRK:

Inwardly rectifying K+-channel

Kv:

Voltage-gated K+-channel

LUMO:

Lowest unoccupied molecular orbital

MLR:

Multiple linear regression

MOPAC:

Molecular orbital partial atomic charge

PCA:

Principal component analysis

PCO:

Potassium (K+)-channel opener

PCR:

Principle components in multiple linear regression

PLS:

Partial least square

QSAR:

Quantitative structure–activity relationship

QSTR:

Quantitative structure–toxicity relationship

RASMC:

Rat aortic smooth muscle cells

WHIM:

Weighted holistic invariant molecular descriptors

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Acknowledgements

Authors thank Director, CDRI for extending the library facility and Dr. Shreekant Deshpande, Faculty of Pharmacy, Hygia Institute of Pharmaceutical Education and Research, Lucknow, for critical reading of the draft manuscript (CDRI communication No. 8062).

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Authors and Affiliations

  1. Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow, 226 001, India

    Yenamandra S. Prabhakar

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  1. Brij K. Sharma
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  2. Prithvi Singh
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  3. Yenamandra S. Prabhakar
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Correspondence to Yenamandra S. Prabhakar .

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  1. , Dept. of Pharmaceutical Technology, Meerut Institute of Engineering and Tech, Baghpat Road Bypass Crossing, Meerut, 250005, India

    Satya Prakash Gupta

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Sharma, B.K., Singh, P., Prabhakar, Y.S. (2011). Advances in Structure–Activity Relationship Studies on Potassium Channel Modulators. In: Gupta, S. (eds) Ion Channels and Their Inhibitors. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-19922-6_8

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