Hypertension, also referred to as high blood pressure, is a condition in which the arteries have persistently elevated blood pressure. According to a medical dictionary , hypertension means "High blood pressure; transitory or sustained elevation of systemic arterial blood pressure to a level likely to induce cardiovascular damage or other adverse consequences." According to WHO, worldwide, raised blood pressure is estimated to cause 7.5 million deaths, about 12.8% of the total of all deaths. Current antihypertensive medications, control hypertension partially and most of them have serious side effects.
To minimize number of hypertension patient, researchers from University of California San Diego has designed new compounds that mimic those naturally used by the body to regulate blood pressure.
For their study researchers studied the properties of the hormone catestatin. Catestatin acts as the gatekeeper for the secretion of catecholamines -- hormones that are released into the blood during times of physical or emotional stress. Catestatin binds nicotinic acetylcholine receptors found in the nervous system, and developed a pharmacophore model of its active centers. To design a drug that mimics the action of catestatin, that would allow people to control the hormones that regulate blood pressure, they also screened a library of compounds for molecules that might match the 3D "fingerprint". Researchers created a three-dimensional model of the most important binding centers -- the pharmacophore model as in figure.
Catestatin-mimic pharmacophore model. Pharmacophore centers correspond to hydrophobic residues Leu5, Phe7, and Phe14; and positively charged residues Arg8, Arg10, and Arg15. Green circles represent hydrophobes and aromatic/hydrophobic features, while dark-blue circles represent NCN+ groups/cations/H-bond donors. Ribbon diagram and three-dimensional residue structures belong to superimposed catestatin. (Credit: Valentina Kouznetsova, UC San Diego)
After screening about 250,000 3D compound structures in the Open NCI Database, they discovered seven compounds that met the requirements, and tested those compounds in live cells to gauge their effects on catecholamines. Based on their findings, they tried one compound (TKO-10-18) on hypertensive mice, and showed that this compound produced the same anti-hypertensive effect as catestatin.
Researched is published online this month in Bioorganic & Medicinal Chemistry.
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