SYNTHESIS AND ANTICONVULSANT STUDIES OF 3 ISOMERS OF 4[(DIMETHYLPHENYL)AMINO]-4-OXOBUTENOIC ACID
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CHAPTER ONE
1.0 INTRODUCTION
1.1 Background
Epilepsy is a chronic disorder of the brain that affects people in every country of the world. It is characterized by recurrent seizures from episodic discharge. Seizures are brief episodes of involuntary shaking which may involve a part of the body (partial) or the entire body (generalized) and sometimes accompanied by loss of consciousness and control of bowel or bladder function. (WHO, 2016) Brain cells communicate with each other and other cells through electrical signals. Seizure occurs when there is excessive electrical discharge from a group of brain cells (WHO 2016) There is no recognized cause of epilepsy, although it may develop following a brain damage caused by infection, tumor, trauma or other kinds of neurological defects and diseases (Rang et al., 2007).
Over 50 million people have been estimated to have epilepsy in the world of which about 75% or more are in developing countries and underdeveloped countries with little or no access to proper medical services (Meinardi et al., 2001; Ngugi et al., 2010; WHO 2016). Communication and coordination of the entire body is partly by the nervous system which consists of the brain the spinal cord. This system is consisting of millions of microcellular unit called the neuron (a nerve cell). This neuron as seen in figure 1.1 consists of a cell body, an axon (branch) and dendrites which connect one neuron to another at a junction called the synapses by communication of electrical signals across channels in the nerve cell membrane (Shield et al., 2000) Figure 1.1 The Neuron with the Nerve Cell Body, Dendrites and Axon (Wikipedia) Transmission from one neuron to another via the synapse is facilitated by a neurotransmitter. Some could be excitatory such as glutamate while others such as GABA are inhibitory to the joining neuron there by electrically inhibiting signals from passing down the neuron it is by this chemical and electrical pathway that millions of neurons communicate and function normally in the brain (Shield et al., 2000).
Along the axon of a neuron from outside are calcium ions while from within are Na and Cl ions which are controlled by gated channels. This complex of ions and its relative balance makes the axon depolarized as such no message or impulse is transmitted. On receipt of a signal, there is a potentiation of the axon called action potential which opens the gated channels and thereby allowing influx of calcium ion and outflux of sodium and chloride ion. Thereby, giving way for the transmission of impulses.
The relative inability of the brain and the spinal cord to maintain the balance between the chemicals in the synapse and the electrical impulses result in an uncoordinated electrical and chemical trigger within the brain thus resulting in seizures. Antiepileptic drugs work by ways of either decreasing excitation or enhancing inhibition. Specifically, antiepileptic drugs (AEDs) acts via the following ways; alteration of chemical transmission between neurons (GABA, glutamate), alteration of electrical activity in the neuron (Na, Ca, K, Cl) and via unknown mechanisms
1.2 Statement of Research Problem
The estimated proportion of the general population with active epilepsy (i.e. continuing seizures or the need for treatment) at a given time is between 4 to 10 per 1000 people (WHO, 2016). Epilepsy is a public health issue especially in developing countries and is limited to certain factors such as; methods of therapy such as surgery, vagal nerve stimulation, deep brain stimulation, avoidance therapy , alternative medicine and dietary changes have been employed to treat epilepsy, but anti epileptic drugs (AEDs) remain the most widely utilized treatment strategy (Gerlach and Krajewski, 2010). However, pharmacotherapy of epilepsy is confronted with four major problems –
- About 20-40 percent of epilepsy patients do not respond at all to currently available AEDS (Pavia et al., 1987; Avanzini and Fanceschetti, 2003; Sirven , 2016).
- Currently available AEDS are associated with toxicity and serious side effects, notably cognitive dysfunction, ataxia, behavioral disorder, hepatotoxicity, gingival hyperplasia megaloblastic anaemia and teratogenesis (Theunissen et al., 1994; Tomson et al., 1997; Zahn et al., 1998; Battino et al., 2000).
- Continous medication is necessary even after the seizures have long been suppressed (Sasa, 2006).
- Available AEDS merely treat the symptoms and not the disorder (Sasa, 2006).
1.3 Justification of the Study
The impact of epilepsy to the society goes beyond just the patient but the family and indirectly the society. Stigma has also long been recognized as a major burden to people with epilepsy and their families (Temkin, 1971; Whitman, 1986). In Asia and India the discovery of epilepsy in a couple is a reason for nullification of marriage (WHO 2016). The nature and degree of this stigma vary depending on an individual’s premorbid/ baseline status within society and the societal conceptualization of the condition. (Morrell, 2002, Baskind, 2005; Jacoby et al., 2005).
Epilepsy also has serious physical, psychosocial and economic consequences on the concerned persons and their families.Reports from West Africa generally indicate that people believe seizures to be contagious, could be spread by saliva, urine, feaces or flatus expelled during convulsions (Rwiza et al., 1993; Andermann, 2000). Furthermore, children and adolescent with epilepsy are at increased risk of emotional, behavioral and cognitive disorders (Alwash et al, 2000; Oostrom et al., 2000; Adewuya and Ola, 2005). Indeed the burden produced by epilepsy is enormous and of global concern. Yet, a large proportion of the patients particularly in the developing world go without treatment. This informed the establishment of the Global Campaign against Epilepsy by the World Health Organization (WHO), the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) in the year 2002. This study is aimed at addressing the above problems via research and exploration of other anticonvulsant agent through the synthesis and evaluate the 3 isomeric forms of the synthesized compounds (which are derivatives of carboxamide). To the best of our knowledge the existence, synthesis and anticonvulsants evaluation of these compounds have not been reported in any literature as at the time of commencement of this work. Therefore, this research work is the first of its kind.
1.4 Aim of the study
To synthesize and screen the anticonvulsant activities of 4-[(2, 4- dimethylphenyl) amino]-4-oxobutenoic acid, 4-[(2, 5- dimethylphenyl) amino]-4-oxobutenoic acid and 4-[(2, 6-dimethylphenyl) amino]-4-oxobutenoic acid.
1.5 Objectives of the Study
- To Synthesize and characterize the isomeric forms of the compound
- To establish acute toxicity as well as the neurotoxicity of the synthesized compound
- To evaluate the anticonvulsant activity of the synthesized compounds using maximal electro shock (MES) and subcutaneous pentylenetetrazol (scPTZ) test models.
1.6 Research Hypothesis
The synthesized compound, viz: 4-[(2, 4- dimethylphenyl) amino]-4-oxobutenoic acid, 4-[(2, 5-dimethylphenyl) amino]-4-oxobutenoic acid and 4-[(2, 6- dimethylphenyl) amino]-4-oxobutenoic acid poses anticonvulsant activity.
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