SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF SOME CALCIUM CHANNEL BLOCKER THIOSALICYLAMIDE DERIVATIVES AS ANTIHYPERTENSIVE AGENTS

Pharma courses

Pharma Admission

pharma courses

pharma admission



About Author:
ABHISHAK SINGH PARMAR,
M.PHARMACY (MEDICINAL AND PHARMACEUTICAL CHEMISTRY),
B.R.NAHATA COLLEGE OF PHARMACY,
MANDSAUR (M.P).
*abhishakparmar@gmail.com

1. INTRODUCTION
1.1 Medicinal and Pharmaceutical chemistry

It is a discipline at the intersection of chemistry and pharmacology involved with designing, synthesizing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and development of new chemical entities suitable for therapeutic use. It also includes the study of existing drugs, their biological properties, and their quantitative structure-activity relationships (QSAR). Pharmaceutical chemistry is focused on quality aspects of medicines and aims to assure fitness for the purpose of medicinal products. Compounds used as medicines are overwhelmingly organic compounds including small organic molecules and biopolymers. However, inorganic compounds and metal-containing compounds have been found to be useful as drugs. For example, the cis-platin series of platinum-containing complexes have found use as anti-cancer agents.1

Medicinal chemistry is a highly interdisciplinary science combining organic chemistry with biochemistry, computational chemistry, pharmacology, pharmacognosy, molecular biology, statistics, and physical chemistry.

REFERENCE ID: PHARMATUTOR-ART-1629

Discovery
The first step of drug discovery involves the identification of novel active compounds, often called "hits", which are typically found by screening many compounds (compound library) for the desired biological properties. While a number of approaches toward the identification of hits exist, the most successful of techniques relies on chemical and biological intuition developed through years of rigorous chemical-biological training. Other sources of hits can come from natural sources, such as plants, animals, or fungi. Hits may originate also from random chemical libraries, such as those created through combinatorial chemistry or historic chemical compound collections that are tested en-masse against the biological target in question.1

Optimization
Another step in drug discovery involves further chemical modifications in order to improve the biological and physiochemical properties of a given candidate compound library. Chemical modifications can improve the recognition and binding geometries (Pharmacophore) of the candidate compounds, their affinities and pharmacokinetics, or indeed their reactivity and stability during their metabolic degradation. The quantitative structure-activity relationship (QSAR) of the Pharmacophore play an important part in finding lead compounds, which exhibit the most potency, most selectivity, best pharmacokinetics and least toxicity. QSAR involves mainly physical chemistry and molecular docking tools (CoMFA and CoMSIA), that leads to tabulated data and first and second order equations. There are many theories, the most relevant being Hansch's analysis that involves Hammett electronic parameters, steric parameters and logP (lipophilicity) parameters.1

Development
The final step involves the rendering the lead compounds suitable for use in clinical trials. This involves the optimization of the synthetic route for bulk production, and the preparation of a suitable drug formulation.1

1.2 Drug design concept
Paul eldritch provided rationality to modern drug research. “Prontosil” an antibacterial agent provided the concept of drug design to medicinal chemist. The drug design is based mainly on the modification of lead molecule which suffers from many unwanted side effects.  The efficiency of a lead molecule can be increased by High through out screening (HT.P.S) technique with utilizes cell line culture system with Enzyme linked immune system assay (E.L.I.S.A.) and receptors molecules which are derived from gene cloning.

The new techniques like molecular graphics and computational chemistry provides new chemical structure which helps in making potent new drugs.2

The various stages covered in medicinal chemistry are:-
(1) First stage involves the identification of new active compounds known as lead         molecules. The lead molecules are derived from   natural substances, organic chemical reactions and biotechnological process.
(2) In the second stage the lead molecule is further optimized to prepare a compound with improved biological activity, selectivity, potency and reduced toxicity.
(3) The third stage involves optimization of method of production to produce drug in bulk amount and further modification of pharmacokinetic and pharmaceutical properties of active substance to make it a clinically useful compound.

1.3 Hypertension
Hypertension is defined as condition in which systolic and or diastolic blood pressure exceed above 140/90mm Hg, an agent that lowers blood pressure is called the antihypertensive agent. The  most desired action is slow reduction of blood pressure with prolonged effect further increased doses should cause a more prolonged effect rather than a more pronounced fall in blood pressure finally the drug should be active after oral administration because they would be used for extended periods.3

In today’s era of globalization, characterized by hurry, worry, and curry, the incidences of cardiovascular diseases are on the rise. Hypertension is a condition where the blood pressure is constantly higher than normal. This poses a serious health risk because it forces the heart to work extra hard. Constantly higher blood pressure can damage the coronary arteries, the brain, the kidneys, and the eyes. Hypertension is a major cause of strokes and heart attacks.4

· Types of Hypertension

(1)Primary hypertension
Despite many years of active research, there is no single major factor that can be attributed to primary hypertension. There is a natural progression of the disease which suggests that an early elevation in blood volume and cardiac output might initiate subsequent changes in systemic vasculature (increased resistance).

Though the specific cause for this type is unknown, almost 90% of the total hypertension cases are of this type. It is also called as ‘essential or idiopathic’ hypertension.4

(2) Secondary hypertension
There are many known conditions that can cause secondary hypertension also known as ‘inessential hypertension’. Regardless of the cause, arterial pressure becomes elevated either due to increase in cardiac output or increase in systemic vascular resistance or both. When cardiac output is elevated, it is generally due to either increased neurohumoral activation of the heart or increased blood volume. The cause may be any of these: renal artery disease, eclampsia of pregnancy or pheochromocytoma. Only around 10% of the total cases belong to this category.4

· Causes and pathological risks of uncontrolledHypertension
High blood pressure is a potential risk factor for cardiovascular diseases, independent of the presence or absence of other risk factors, for example, smoking,diabetes, and/or hypercholesterolemia. The other factorssuch as genetics, age, sex, race, diet, and environmentalfactors (e.g., stress and physical activity), also playimportant role in elevation of the blood pressure.

· Etiology of hypertension
However the hypertension may arise secondary to many diseases but the hypertension is known to be due to genetic history of the family. If the parents suffer from hypertension then in children hypertension may occur. It is seen that more than 90% of the black people are suffered from hypertension than whites. Thus it is found more in black peoples. It occurs more in middle age men than in middle age women. Environmental factors like working in stressful lifestyle, excess sodium intake, obesity, and smoking, all further increases chances of hypertension.5

· Control of blood pressure
Blood pressure in its simplest term is the force of pumping of heart action, working against the resistance provided by the blood vessels. Body has a special ‘blood pressure system’. The purpose of this system is to maintain blood flow to all the tissues of the body at rest or during movements (figure-1). Table -1 depict the delicate coordination between cardiovascular system and the sympathetic nervous system involving some important organs like kidneys, brain, adrenals, and heart, to regulate the blood pressure. Genetic and environmental factors cause imbalance in this and cause hypertension.4

· Mechanism for controlling blood pressure
Arterial blood pressure is controlled with a narrow range to provide a sufficient perfusion of the tissues without causing damage to the vascular system, specially the arterial intimae. The arterial blood pressure is directly proportional to the product of cardiac output and peripheral vascular resistance. In normal and abnormal hypertensive individual both the cardiac output and peripheral resistance are regulated mainly by two overlapping controlled mechanisms. In controlling of blood pressure Benzothiazepine and thiosalicylamide analogous play important role by the blocking calcium channel present in blood vessels. The baroreflexes are mediated by the sympathetic nervous system and the rennin angiotensin- aldosteron system. Most of the antihypertensive drugs lower the blood pressure by reducing cardiac output, or decreasing peripheral resistance.

1.4  Antihypertensive drugs
History and classification
.
The discovery of most of our current antihypertensive drugs did not involve the target design of molecules to modify a blood pressure control system. Most of the drugs have evolved out through conventional synthesis and biological evaluation processes based on QSAR studies.The currently used antihypertensive drugs are classified into seven broad categories.4

Table no.1 Classes of currently established drugs for the treatment of hypertension

Class

Chemical

Examples of drugs

Diuretics

Thiazide type


Potassium sparing type

Looptype

Chlorothiazide, Chlorthalidone, Bendroflumethiazide, Trichlormethiazide

Spironolactone, Amiloride, Triamterene

Furosemide, Ethacrynic acid, Bumetanide, Torasemide

Β-Blockers

Non-selective (β1/ β2)


Selective β1

Propranolol, Timolol, Nadolol, Pindolol, Cartetolol

Atenolol, Betaxolol, Metaprolol, Acebutolol, Tozalol

ACE inhibitors


Captopril, Enalapril, Lisinopril, Fosinopril, Ramipril

Ca2+ blockers

Dihydropyridine, Phenyalkylamines Verapamil, Gallopumil, Benzothiazepines, thosalicylamide.

Nifedipine, Nicardipine, Felodipine, Amlodipine

Diltiazem, Thisalicylamide derivative

 α1-Adr antagonists


Prazosin, Doxazosin, Terazosin, Labetolol

 α2-Adr agonists


Clonidine, Guanafexine, Guanabenz

Miscellane-ous


α-Methyldopa,Euronalblockers(Bretilium, Guanethedine),Rauwolfia and its alkaloids, (Reserpine, Deserpine, Rauwolfia whole root),Ganglionic blockers (Guanadrel, Mecamylamine, Hexamethonium),

Non-specific vasodilators (Hydralazine, Nitroprusside, Diazoxide, Minoxidil.

1.5 Calcium channels                                                                               
Voltage-gated calcium channels are integral membrane proteins that allow calcium ions to flow into the cell cytoplasm from the extracellular milieu, in response to membrane depolarization. This class of ion channel is found in virtually all types of excitable cells, ranging from neurons and glial cells to muscle cells. The functional inventory of calcium channels is equally broad, spanning from triggering of muscle contraction over control of neurotransmitter release to electrical excitation (calcium action potentials). The diversity of calcium channel function is reflected in their molecular heterogeneity: Several genes, encoding biophysically and pharmacologically distinct types of calcium channels, have been cloned and characterized functionally. These different types of calcium channels play specialized roles in cellular function; for instance, L-type calcium channels mediate muscle contraction and N- and P/Q-type calcium channels control neurotransmitter release.12

·         Regulation of intracellular calcium levels
Most of the calcium ions  in a resting cell is sequestered in organelles, particularly the endoplasmic or sarcoplasmic reticulum (ER or SR)  and the mitochondria , and the free calcium ion is kept to a low level, about 10-7 M. The calcium ionsconcentration in tissue fluid is about 2.4 Mm, so there is a large concentration gradient favouring Ca2+ entry. Free calcium ion is kept low (a) by the operation of active transport mechanisms that eject cytosolic Ca2+ through the plasma membrane and pump it into the ER , and (b) by the normally low  Ca2+   permeability of the plasma and ER membrane. Regulation of free calcium ion involves three main mechanisms:                                                                      1. Control of Ca2+ entry
2. Control of Ca2+ extrusion
3. Exchange of Ca2+ between the cytosol and the intracellular stores.7

Figure -2 Regulation of intracellular calcium7

 Calcium entry mechanism                                                                               There are four main routes by which   Ca+2 enter cells across the plasma membrane: 
I.Voltage-gated calcium channel 
II. Ligand-gated calcium channel
III. Store–operated calcium channel  
IV. Na+- Ca+2 exchange.7

I. Voltage- gated calcium channel
Voltage-gated calcium channels are integral membrane proteins that allow calcium ions to flow into the cell cytoplasm from the extracellular environment, in response to membrane depolarization.In  excitable  cells,  voltage-dependent  calcium  channels  (VDCCs) are  responsible  for  the  increase  of  intracellular  free  calcium  concentration, by  the  influx of  extracellular  Ca+2 across  the  plasma  membrane .In  non-excitable  cells,  an  increase  of intracellular  free  calcium  concentration  results:  (i) from  the  activation  of  intracellular Ca+2  stores,  such  as endoplasmatic  reticulum,  and (ii)  from  a  receptor-mediated  Ca+2  entry  across  the plasma  membrane.8

Voltage-gated calcium channel have been classified their electrophysiological and pharmacological properties and are generally divided into low-threshold (T-type) and high threshold (L-, N-, P/Q- and R-types). The L-, N-, P/Q- and R-type channels typically activate at membrane potentials near - 30 mV and display diverse kinetic, voltage-dependent and pharmacological properties.12

The subtypes vary with respect to their activation and inactivation kinetics, their conductance, and their voltage threshold for activation, their conductance and their sensitivity to blocking agents as summarized in table1(rang and dales).These different types of calcium channels play specialized roles in cellular function; for instance, L-type calcium channels mediate muscle contraction and N- and P/Q-type calcium channels involved in neurotransmitter release and T type  channel mediate Ca+2  dependent functions such as  regulation of other channel ,enzyme etc.7

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE


 

Pages

FIND MORE ARTICLES