BARBITURATES

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SAR OF BARBITURATES: 

SAR OF BARBITURATES By. Jyotirmoy Das Choudhury M.Pharm 2nd semester Pharmacology Department. RCPHS

Content….: 

Content…. Introduction. History. Types. Synthesis. Mechanism of Action. Uses. Parent compound. Requirement of SAR Study. SAR Study. Conclusion. References.

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INTRODUCTION

Barbiturates: 

Barbiturates All derivatives of Barbituric acid Depressants of the central nervous system (CNS) that impair or reduce the activity of the brain by acting as a Gamma Amino Butyric Acid (GABA) potentiators Categorized as hypnotics and also called “downers” Produce alcohol like symptoms such as impaired motor control (ataxia), dizziness, and slower breathing and heart rate

History: 

History Barbituric acid was first created in 1864 by a German scientist named Adolf von Baeyer. It was a combination of urea from animals and malonic acid from apples . Its first derivative utilized as medicine was used to put dogs to sleep but was soon produced by Bayer as a sleep aid in 1903 called Veronal Phenobarbital was soon discovered and marketed as well as many other barbituric acid derivatives Prescribed as sedatives, anesthetics, anxiolytics , and anti- convulsants Also popular to abuse because of their alcohol like effects

Types : 

Types Barbituric Acid Amobarbital Pentobarbital Short acting Intermediate acting Long-Acting Thiopental sodium Ultra shortacting Phenobarbital

Synthesis: 

Synthesis Barbituric acid is synthesized by a condensation reaction that results in the release of H 2 O (dehydration) and the heterocyclic pyrimidine Further substitution of side chains on the ring produce the pharmacologically active barbiturates Malonic Acid Urea Barbituric Acid C2H5—ONa

Mechanism of Action: 

Mechanism of Action GABA binding site Barbiturate binding site Barbiturates potentiate the effect of GABA at the GABA-A receptor. The GABA-A receptor is a ligand gated ion channel that allows for the flow of Cl through the membrane in neurons. GABA is the principle neurotransmitter for this receptor which upon binding causes the channel to open and creates a negative change in the transmembrane potential. This makes it an Inhibitory neurotransmitter GABA

Mechanism of Action: 

Mechanism of Action Barbiturates potentiate the effect of GABA by binding to the GABA-A receptor at a nearby site and increasing the chloride flow through the channel. Barbiturates also block the AMPA receptor which is sensitive to glutamate, the excitatory neurotransmitter. Glutamate performs the opposite effect from GABA restricting ion flow and increasing the transmembrane action potential of the neuron. By blocking this action Barbiturates serve to increase the duration of the receptor response to GABA and extend the depressed condition of the cell.

Uses: 

Uses Barbiturates have been use in the past to treat a variety of symptoms from insomnia and dementia to neonatal jaundice. They have largely been replaced with drugs such as benzodiazepine due to their propensity for addiction and reduced effect over extended use. Still widely used to treat most seizures including neonatal seizures. Used when benzo class drugs fail or in underdeveloped countries. Cannot be used for treatment of absence seizures.

Parent Compound: 

Parent Compound

Reason Behind to Study SAR: 

Reason Behind to Study SAR Barbituric acid itself does not possess any hypnotic properties. It is only when the two active hydrogen atoms at position 5 : 5 have the appropriate substituent ( e.g., alkyl or aryl groups) that the ‘hypnotic activity’ is produced by the compound. To increase the therapeutic activity. To modify the Onset of Action. To modify the Duration of Action.

Structure-Activity Relationship: 

Structure-Activity Relationship The following cardinal points must be taken into consideration with respect to the structure-activity relationship amongst the barbiturates. These are : ( i ) The total number of carbon atoms present in the two groups at carbon 5 must not be less than 4 and more than 10 for the optimal therapeutic results. Contd...

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(ii) Only one of the substituent groups at position 5 may be a closed chain. Methylepentobarbital Contd...

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(iii) The branched chain isomer exhibits greater activity and shorter duration. The greater the branching, the more potent is the drug (e.g., pentobarbital > amobarbital ). Pentobarbital Amobarbital Contd...

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(iv) Double bonds in the alkyl substituent groups produce compounds more readily vulnerable to tissue oxidation ; hence, they are short-acting. Pentobarbital Sodium Contd...

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(v) Aromatic and alicyclic moieties exert greater potency than the corresponding aliphatic moiety having the same number of carbon atoms. Methylepentobarbital Contd...

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(vi) Short chains at carbon 5 resist oxidation and hence are long-acting. Long chains are readily oxidized and thus produce short-acting barbiturates. Pentobarbital Sodium Barbital Contd...

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(vii) Inclusion of a halogen atom in the 5-alkyl moiety enhances activity. (viii) Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and SO3H) in the 5-alkyl moiety reduces potency considerably. (ix) Methylation of one of the imide hydrogens enhances onset and reduces duration of action Methylepentobarbital Contd...

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(X ) The replacement of O-atom with an S-atom, at C- 2 position of the barbiturates significantly enhances the lipid solubility profile. The resulting modified versions of the barbiturates thus obtained exert a rapid onset of activity by virtue of the fact that they attain maximal thiobarbiturate -brain levels. Therefore, such drugs as ‘thiopental sodium’ find their profuse and abundant application as ‘intravenous anaesthetics’ . Thiopental sodium Contd...

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(xi) Inclusion of more sulphur atoms (e.g., 2, 4-dithio ; 2, 4, 6-trithio) decreases activity. Likewise introduction of imino group(s) into the barbituric acids abolishes activity (e.g., 2-imino ; 4-imino ; 2, 4-diimino and 2, 4, 6-triimino). Contd...

Conclusion….: 

Conclusion…. SAR study is unavoidable to make a compound perfect for exerting desired pharmacological action. To improve pharmacokinetic & pharmacodyanamic parameters. To reduce toxicity.

References…: 

References… Ashutosh Kar ; Sedative & Hypnotics; 2009; Fourth Edition; Page : 171-197. Alfred Goodman Gilman; The Pharmacological Basis of Therapeutics; Dennis S. Charney , S. John Mithic ; Sedative & Hypnotics; 2001; 10 th Edition; Page : 414-415.

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Mail id: jdc_pharma@yahoo.in / jdc_13@rediffmail.com/ jdc_pharma@hotmail.com