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ISSN: 0975-8585 November–December 2017 RJPBCS 8(6) ISSN: 0975-8585 Research Journal of Pharmaceutical, Biological and Chemical Sciences Identification of the Antagonistic Effect of (-) Carvone On Ca2+ Channel, Histamine and Acetylcholine-Muscarinic Receptors in Isolated Smooth Muscle Preparation: An In Vitro and In Silico Correlation Study M Mohamed Shabi1, Liniya Sunny2, U Aravind Krishnan2, Vishnu S2, and Vasudeva Rao Avupati3,*. 1Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, UCSI University College, No. 1 Jalan Menara Gading, Taman Connaught, Cheras, 56000 Kuala Lumpur, Malaysia 2Amrita School of Pharmacy, AIMS Health Sciences Campus, Kochi, Kerala, India. 3Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 18 Jalan Jalil Perkasa, Bukit Jalil, 57000 Kuala Lumpur, Malaysia ABSTRACT Carvone is a monoterpene found mainly in caraway seeds, dill and fennel fruits. These are used as a folk remedy for diarrhoea, acidity and other gastric disorders. The study was designed to evaluate the pharmacological effect of (-)Carvone mediated through L-Type voltage dependant Calcium [Ca++] channel, Histamine [H1] and Muscarinic [M3] receptor on Isolated smooth muscle preparation by Dale’s apparatus and its in –silico correlation. There are two phases in this study, in phase one, the antagonist effect of (-)Carvone ++ on H1, M3 receptor and L-Type voltage gated Ca channel on isolated chicken ileum preparation by using Dale’s apparatus. In phase two, to gain better insight for the interactions between the compounds and their respective targets along with (-) Carvone, we docked and validated its results based on scoring function using AUTODOCK 1.5.6. Here (-)Carvone showed ,the binding energy value of -7.53 Kcal/mol for Ca++ protein, -6.33 Kcal/mol for H1 receptor, -5.82 Kcal/mol for M3 receptor. It involves the active site residues and a crucial H- Bond interaction of key residues of LYS97, TYR431 and SER151 respectively. This results confirms that (- )Carvone docks well when compared to standard Ca++ blockers, anti-Histaminic drugs and anti-muscarinic drugs. The phase one study revealed that, the maximum inhibitory action was produced by (-)Carvone against Calcium ion, followed by acetylcholine and Histamine on isolated smooth muscle . The study shows, (-)Carvone ++ produces antagonist effect by multi receptor mechanism against H1, M3 receptor and Ca so it may inhibit eosinophil, chemotaxis, LTB4 release and various effects on many excitable cells of the body such as cardiac muscle, smooth muscles of blood vessels or neurons. The correlation of in –vitro and in-silico results suggested that (-)Carvone is useful for the treatment of various metabolic disorders and GI related disorders. Keywords: (-)Carvone, Dale’s apparatus, Calcium channel, Histamine, Muscarinic receptor, AUTODOCK 1.5.6. *Corresponding author November–December 2017 RJPBCS 8(6) Page No. 328 ISSN: 0975-8585 INTRODUCTION The term receptor is used in pharmacology to denote a class of cellular macromolecules that are concerned specifically and directly with chemical signaling between and within cells. Combination of a hormone, neurotransmitter, or intracellular messenger with its receptor(s) results in a change in cellular activity. Hence, a receptor must not only recognize the particular molecules that activate it, but also, when recognition occurs, alter cell function by causing, for example, a change in membrane permeability or an alteration in gene transcription. With the concept of the receptor established, pharmacologists turned their attention to understanding the quantitative relationship between drug concentration and the response of a tissue. This entailed first, finding out how the fraction of binding sites occupied and activated by agonist molecules varies with agonist concentration and second, understanding the dependence of the magnitude of the observed response on the extent of receptor activation. The majority of isolated compound show a remarkably high correlation of structure and specificity to produce pharmacological effects. Experimental evidence indicates that drugs interact with receptor sites localized in macromolecules. In most cases a rather specific chemical structure is required for the receptor site and a complementary drug structure. Slight changes in the molecular structure of the drug may drastically change specificity [1]. Organ isolation and tissue preparation Isolated organs and tissue preparations have been extensively used for measuring effects due to receptor-agonist interactions, as well antagonist. The isolated ileum is probably the most widely used model in experimental pharmacology [2] Guinea pigs, rabbits and rats are usually the common sources of isolated tissues. Mice are also sometimes used for the purpose, while cats and dogs are too big to be sacrificed just for a piece of tissue [3]. The use of isolated preparations becomes an essential part in experimental pharmacology to understand the effects of a drug, especially in academics. The Committee for the Purpose of Control and Supervision of Experiments on Animals [CPCSEA] [4] is an authority which monitors animal experiments conducted in institutions through ethics committees and is mainly concerned with promoting the human care of animals used in biomedical and behavioral research. The use of an alternative source serves the purpose of decreasing, if not completely eliminating, the killing of laboratory animals just for a strip of tissue. The isolated strips of intestine are the most commonly used smooth muscle preparation, especially the ileum which possesses muscarinic, histaminic, adrenergic, serotonergic and GABAergic receptors. The presence of muscarinic receptors in goat ileum has been reported. It is both ethical and economical in using goat ileum for this purpose [5]. The purpose of bioassay is to ascertain the potency of a drug and hence it serves as a quantitative part of any screening procedure. Several methods are used to determine the potency of a drug substance with minimal error. The investigation sought to examine the suitability of the chicken ileum for doing pharmacological basic receptor finding. The study designed for pharmacological evidence of (-)Carvone ++ mediated through L-Type voltage dependant Ca channel, H1and M3 receptor in isolated smooth muscle preparation and its in- silico correlation. MATERIALS AND METHODS Tissue selection The drug was formulated into a suitable dosage form and used for biological study. The study needs to be carried out in-vitro and therefore no need of laboratory animals which has to be eventually sacrificed, for performing the in-vitro study. However, the chicken ileum is a tissue that is easily available from slaughter house and animal need not to be sacrificed for experimental purpose [6]. Chemicals & Drugs (-)Carvone used in this experiment was from Sigma, St. Louis, USA. Histamine was purchased from Himedia Laboratories, Mumbai, India. Acetylcholine was purchased from Research Lab Fine Chemicals, Mumbai, India. Diltiazem was purchased from Torrent pharmaceuticals, Mehsana, India. Pheniramine was purchased from Aventis Pharma limited, Gujarat, India. Atropine was purchased from Titan Biotech, Bhiwadi, November–December 2017 RJPBCS 8(6) Page No. 329 ISSN: 0975-8585 India. Physiological salt solution compositions were purchased from NICE chemicals, Kerala, India. All the chemicals used in this experiment were of analytical grade. In-Vitro Method In-vitro study was conducted using Dale’s apparatus. In-Silico Material AUTODOCK is a suite of automated docking tools. It is designed to predict how small molecules, such as substrates or drug candidates, bind to a receptor of known 3D structure. The structures of compounds were obtained from protein data bank and energy minimization was done using Argus lab, to obtain local minimum structure. Such energy minimized structures were considered for Docking and corresponding Pdbqt files were prepared in Auto-dock 1.5.6 [7]. Research Methodology In- Vitro Methods Physiological salt solution composition The superfusing Tyrode solution (pH 7.4; Temperature, 37± 1 ºC) was prepared using the following constituents in concentrations (in mM) KCl 2.68, NaCl 136.9, MgCl2 1.05, NaHCO3 11.90, NaH2PO4 0.42, CaCl2 1.8 and Glucose 5.55. The superfusion medium was filtered successively through filters, prior to use and was equilibrated with mixture of O2: CO2 (95: 5) at 37 ˚C for 1 hr before and throughout the superfusion. Drug preparation Preparation of Atropine A stock solution of 1µg/ml was prepared using distilled water and was added to the inner organ bath and used as an antagonist of M3 receptor. Preparation of Diltiazem A stock solution of 100µg/ml of Diltiazem was prepared and the following working concentrations were withdrawn from stock solution: 0.02µg, 0.04µg, 0.08µg and 0.12µg and was added to inner organ bath and used as an antagonist of Ca++ channel. Preparation of Pheniramine A stock solution of 100µg/ml of Pheniramine was prepared from which 1ml was withdrawn and made upto 100ml to get 1µg/ml stock solution [8]. The following working concentrations were withdrawn from stock solution: 0.2µg, 0.4µg, 0.8µg, 1.6µg, 3.2µg and 6.4µg and was added to inner organ bath and used as an antagonist of H1 receptors. Preparation of Histamine A stock solution of 100µg/ml was prepared with distilled water. From the stock solution, various doses of the drug was withdrawn at concentration of 10µg, 20µg, 40µg and 80µg and was added to the inner organ bath and used as an agonist of
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