Structure Activity Relationship Studies of Synthesized Diamides on CNS Depression and Sleeping Time Potentiation Effect

 

Nidhi J. Kapadiya¹* and Dhrubo Jyoti Sen²

¹Pacific College of Pharmacy, Pacific Hills, Pratap Nager Extn., Airport Road, Debari, Udaipur-313003, Rajasthan, India

²Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Hemchandracharya North Gujarat University, Arvind Baug, Mehsana-384001, Gujarat, India

*Corresponding Author E-mail: nidhi_kapadiya@yahoo.com

ABSTRACT:

Evaluation of structure activity relationship studies of synthesized diamides on CNS depression and sleeping time potentiation effect through intraperitoneally administration of various doses of test compounds in mg/kg dose in group of male albino mice using propylene glycol as an inert vehicle. The loss of righting reflex and regaining of it was noted for each compounds to determine the sleeping time, injecting drug (diazepam/pentobarbitone) solution to mice, compound + drug solution in the mice and only compound solution to another mice and observed it’s sleeping time potentiation and by plotting the histogram sleeping time has been observed. It has been found that all the teat compounds do not have sleep inducing property. Sleeping time potentiation effect was studied for the teat compounds by using diazepam as benzodiazepine series and pentobarbitone as barbiturate series which show good sleep inducing property. The amide groups of compounds block the GABA receptor and chloride channel and shows longer duration of sleep inducing properrty due to the presence of two amide linkages on male albino mice. Maximum activity was shown by Compound-93 (b) due to the presence of two free –CONH2 linkages and also show more lipid solubility which block GABA receptor ling time produce their effect for longer period of time.

All the compounds exhibited significant CNS depression activity in combination with standard drug diazepam and pentobarbitone.

 

 

 

INTRODUCTION:

Depression is a heterogeneous disorder that affects a person’s mood: physical health and behaviour. Patients with major depression have symptoms that reflect changes in brain monoamine oxidase neurotransmitters¹. It has been reported that gamma amino butyric acid (GABA) is involved in the affective disorders². Upregulation of GABA binding site was observed in rat frontal cortex by repeated administration of different classes of antidepressant³. Subsequently involvements of GABAB receptors have been demonstrated in depression⁴. Anti-depressants drugs like sedative-hypnotic act by various mechanism particularly GABAnergic neurotransmission in the CNS^5,6. Barbiturates⁷ and benzodiazepines⁸ act similarly to produce depression of central nervous system function and behavior. Both classes of drugs enhance the ability of the inhibitory neurotransmitter, gamma amino butyric acid (GABA), to activate a type of receptors known as GABAA receptors⁹.

 

These drugs increase the effectiveness of GABA by altering the receptor so that GABA can bind more easily, an effect known as allosteric regulation. Activation of the GABAA receptor opens as ion channel, allowing negatively charged chloride ions to enter the cell, producing an inhibition of neuronal activity¹⁰.

 

Studies have shown the interest to synthesise a series of substituted diamides, for checking their activity towards CNS depression by using righting reflex method¹¹.

 

MATERIALS AND METHODS:

The CNS depression study of all the synthesised compounds were carried out by administering intraperitoneally the various doses of the test compounds in mg/kg dose in 18 hours fasting male albino mice (20-25 gms) using propylene glycol as an inert vehicle. The loss of righting reflex and regaining of it was noted for each compound to determine the sleeping time and the bioligical response has been tabulated in minutes ± SE (Standard Error) for statistical parameters.

Table-1: CNS depression effect by compounds and diazepam

Samples	Dose (mg/kg)	Sleeping Time (mins)	Sleeping Time (mins)±SE Compound+Diazepam	Potentiation of Sleeping Time (mins)±SE Compounds+Diazepam
87(a)	0.015	0 min	274.16±2.38	166.17±2.38
87(b)	0.015	0 min	249.34±2.27	141.33±2.27
88(c)	0.015	0 min	177.52±3.81	69.5±3.81
89(a)	0.015	0 min	213.33±5.27	105.33±5.27
89(b)	0.015	0 min	227.54±3.81	119.56±3.81
90(a)	0.015	0 min	223.33±5.57	115.33±5.57
93(a)	0.015	0 min	226.00±1.03	118.34±1.03
93(b)	0.015	0 min	308.78±6.41	200.33±6.41
93(c)	0.015	0 min	214.46±6.50	114.54±8.03
93(d)	0.015	0 min	239.66±3.98	131.33±4.09

 

Histogram of CNS depression effect by compounds and diazepam

 

 

Righting reflex method:

Pharmacological screening of sedative hypnotic agents involve abolition of righting reflex in experimental animals. Sleeping time is defined as the period during which the animal has lost its righting reflex i.e. when it does not have the ability to touch a resting surface with all its paws and can be placed on its side or back without rapidly righting itself. The end of the sleeping period is the point at which the animal no longer lies on its side or back but voluntarily returns to its normal up right position. Induction time and sleeping time both have been recorded^11,12.

 

Potentiation of sleeping time using some standard drug:

Prolongation of time of sleep induced by some standard drug like diazepam, pentobarbitone etc. by the use of some agent is a method for investigating effects of newer less potent sedative effect^11,12.

 

The following drugs were used in the study:

87(a): 1,4-bis-(2-phenyl-1H-indol-1-yl)-phenyl-1,4-dione

87(b): 1,6-bis-(2-phenyl-1H-indol-1-yl)-hexane-1,6-dione

88(c): 1 - (4- oxo- 4- (pyrrolidinyl) -butanoyl) –pyrrolidine                 - 2- carboxylic acid

89(a): 5 – methyl - 1- (2 - (5 – methyl - 3- oxo -2- phenyl-2, 3 - dihydropyrazol-1-yl) -2-oxoacetyl) -2-phenyl -1, 2-dihydropyrazol-3-one

89(b): 3-methyl-2-(3-methyl-5-oxo-1-phenyl-2, 5-dihydro-1H-pyrazole-2-carbonyl) -benzoyl) -1-phenyl-1, 2- dihydropyrazol -5 -one

90(a): 1, 1΄ -(1, 4-dioxobutane-1, 4-diyl) –bis - (1H - benzotriazole)

93(a): Succinamide

93(b): Oxamide

93(c): Adipamide

93(d): Phthalamide, Pentobarbitone¹³, Diazepam¹⁴

 

RESULTS:

It has been found that all the test compounds do not have sleep inducing property. Sleeping time potentiation effect was studied for the test compounds by using diazepam as well as benzodiazepine series which has closed chain diamide linkage and our synthesised compounds all have open chain diamide linkage.

 

DISCUSSION:

The righting reflex method has been extensively used for screening of antidepressants. The present study found that all the test compounds do not have sleep inducing property. The test compounds were giving with standard drugs like diazepam and pentobarbitone which showed the CNS depressant activity. The amide griups of compounds block the GABA receptor and chloride channel and shows longer duration of sleep inducing property due to the presence of two amide linkages on male albino mice. Maximum activity was shown by compound-93(b) due to the presence of two free –CONH2 linkages and also show more lipid solubility which block GABA receptor long time and produce their effect for longer period of time.

Table-2: CNS depression effect by compounds and pentobarbitone

Samples	Dose (mg/kg)	Sleeping Time (mins)	Sleeping Time (mins)±SE Compound+Diazepam	Potentiation of Sleeping Time (mins)±SE Compounds+Diazepam
87(a)	0.015	0 min	283.83±4.86	129.83±4.86
87(b)	0.015	0 min	251.83±2.66	97.83±2.66
88(c)	0.015	0 min	180.33±3.49	32.83±7.32
89(a)	0.015	0 min	213.51±4.94	59.52±4.94
89(b)	0.015	0 min	246.67±4.85	92.66±4.85
90(a)	0.015	0 min	240.67±11.96	86.66±11.96
93(a)	0.015	0 min	270.33±10.76	116.33±10.76
93(b)	0.015	0 min	312.31±12.09	158.33±12.01
93(c)	0.015	0 min	208.01±10.32	54.02±10.32
93(d)	0.015	0 min	251.52±8.14	97.51±8.15

 

Histogram of CNS depression effect by compounds and pentobarbitone

 

 

ACKNOWLEDGEMENT:

The author is thankful to Prof. Dr. Dhrubo Jyoti Sen, Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Mehsana, Gujarat who has guided this entire M.Pharm. project work with precious gift of knowledge, moral support, valuable suggestions and encouragement throughout the study.

 

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Received on 11.06.2010        Modified on 25.06.2010

Accepted on 08.07.2010        © AJRC All right reserved