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Group 3 DDMDA Video Project- Temazepam

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This video is going to discuss the drug temazepam temazepam belongs to a family of drugs known as benzodiazepines with each of the members containing the characteristic one for benzodiazepine ring the discovery was indirect tisha’s linked to the works of leo henriques turn back his main aim was to produce an anti-psychotic drug that was better than the current

Alternative the barbiturates serve back focused on making changes to the molecule qin azulene 3 oxide with the aim of introducing an antipsychotic effect subsequently this provided the development of 40 new compounds one under log was found to have significant anxiolytic activity resulting from a mistake in the final stages of synthesis but me that amy was used causing

A different reaction to proceed on the 15th of may 1958 simpad patented the drug and named it chlordiazepoxide the first of the benzodiazepine family later on the 24th of february 1960 the job was fda approved the structure and chlordiazepoxide was simplified to produce the second benzodiazepine diazepam lorazepam is a more powerful drug and was synthesized by stern

Back in 1959 and was then commercialized by the december of 1963 it was from diazepam that temazepam and many of the other benzodiazepines on the market today were synthesized temazepam is a 3 hydroxy analog of diazepam and an active metabolite in the united states temazepam falls under the trade name of rostral and was initially marketed by sanders in february of

1981 the synthesis of the from kapur uses a benzophenone as a raw material which is isetta lated on the annalee no nh 2 with a clora acetyl chloride with doc same and sodium hydroxide nucleophilic substitution of the chloro group in liquid ammonia under reflux gives the intermedia amino acid i’ll amide which could be cyclized upon heating with pyridine temazepam

Was first synthesized using chlordiazepoxide whereas now modern methods synthesis negates first step and uses the intermediate product to zaza pam as a starting material shortening the process by 30 days the starting material undergoes an methylation by methylation of the nitrogen of the amide group in the first position on the benzodiazepine ring using dimethyl

Sulfate this gives the first intermedia the first intermediate undergoes a set elation by reacting with acetic anhydride to give a second intermediate during which the panofsky reaction takes place the plan offski reaction involves transfer of oxidation from a hitch ratan to an adjacent carbon where an amine and oxide reacts with an acetic anhydride to give an

Aldehyde and a cta light alkaline hydrolysis of the resulting mixture remove the acetyl group leading to the desired temazepam in basic mixture benzodiazepines contain a chiral carbon at position 3 found in vitro in a stereo selective manner to a receptor the pharmacologically active s enantiomer has a hundred to two hundred fold high affinity to the bagging site

Than the r and ancho ma the an enantiomers undergo easy chiral inversion in polar medium and the rates of an enantiomer ization in aqueous solution depend on ph and temperature the racemization mechanism of these drugs is believed to be a fast auto mirai’s asian equilibrium between the ring and the a chiral amino aldehyde forms some studies revealed separation made

Methods like high-performance liquid chromatography however studies on the determination of these chiral drug enantiomers in biological samples are scarce and it is a difficult operation because of the spontaneous carol inversion in polar solvent it was first formulated as a hard gelatin capsule with very slow absorption rate and exhibiting little effects on sleep

Induction with the most effects on sleep maintenance it was then reformulated as a tablet or in soft gelatin form this improves sleep by decreasing the time to sleep induction and improving the sleep maintenance temazepam it’s absorbed slowly and may be given 1 to 2 hours before bedtime temazepam is a schedule three control drug tomorrow pam is specifically used

For insomnia we can see how to mohammed ears to lipinski’s rules allowing for the oral administration with its molecular weight of 301 hydrogen bond donor for hydrogen-bond acceptors a log p-value of two point four seven two concludes marzipan does fit into lipinski’s rules and therefore can be administered orally by tablets capsules or oral solution insomnia

Is the difficulty in falling asleep or remaining asleep in a longitudinal study of 900 children they concluded that if a child has persistent sleep problems between the ages of 5 & 9 they are predicted to have anxiety disorders between the ages of 21 and 26 symptoms of insomnia include daytime effects on fatigue attention concentration and memory impairment

Insomnia is an effects on the sleep system in the brain deep sleep which is also referred to as orthodox sleep takes up to 75 percent of the sleep cycle and the deepest part of the slow-wave sleep the remaining 25% of the sleep cycle is paradoxical sleep which is rapid eye movement peripheral autonomic activity increases during rapid eye movement sleep stimulant

Drugs such as caffeine and nicotine can cause difficulty in getting to sleep withdrawal from alcohol and hypnotic drugs after chronic use can cause rebound insomnia which hence increases rapid eye movement sleep temazepam unlike other benzodiazepines does not produce any active metabolites and it’s considered to have an intermediate half-life of approximately 12

Hours within the context of the benzodiazepine family there arts by enhancing the neuro inhibitory transmitter gaba immune abused ik acid in the brain gaba amina boutique acid will calmly tend to gather occupies up to 40% of all the sinuses in the brain benzodiazepine action activate effects activity in the cerebellum the limbic of the brain and the cerebral cortex

Gaba receptors are hetro pentameric glycoproteins constructed from five of the different subunits in a sequence of alpha beta alpha beta gamma around the poor two types of receptor gamma a and gamma b gaba a is a multi merrik ligand gated chloride ion channel and is also part of a super molecular complex that includes the site for benzodiazepine binding however

Benzodiazepines have no significant effect at the gaba receptor the bearing of temazepam at one of the three allosteric sites of gaba a receptor in the post synaptic membrane modulates the receptor increasing the affinity and action of gaba at the orthostatic receptor site this increases a selective permeability of the own channel to chloride ions allowing more

Chloride ions to enter into the postsynaptic neuron as the equilibrium membrane potential for chloride ions is usually negative at resting potential increasing this permeability hyperpolarizing the membrane as chloride ions enter and thereby reduce the excitability of the neuron leading to the display of the known effects this is the farm full of all of the class-a

Benzodiazepines with the substituents of each varying temazepam structure consists of a chlorobenzene group a hydroxyl group a ketone group a diazepam ring and a phenyl group we are now going to look at the structural activity relationships of somoza pam using the farm kapoor as a reference in renge the aromatic ring is planar and hydrophobic and is therefore

Able to interact with flat hydrophobic areas in the gaba receptor by a pi pi stacking interactions amino acids which may be present in the gum of binding site that can form these pi pi starting interactions with temazepam include v now alanine tyrosine and tryptophan the chloro substituent at carbon number seven of the a ring increases the functional angie lytic

Activity of temazepam there are no substituents at c6 c8 and c9 in vitro synthesis as addition of substituents at these positions on the a ring are known to decrease and the illicit activity of temazepam the b ring the person accepting group is a structural requirement for binding of the ben does appear liggins to the gaba a receptor in temazepam the oxygen in

The a might can act as a hydrogen bond acceptor whoever the nitrogen cannot as its lone pair of electrons are conjugated into the pi system of the amide bond and making them unavailable for hydrogen bonding the proton accepting group the oxygen interact with the histidine residue this acts as a proton source in the gaba a subunit optimal affinity occurs when the

Proton accepting group is at position two of the b ring and hence the position of the carbonyl in the bering structure temazepam the hydroxyl group at position 3 has comparable potency to non hydroxylated analogs and is excreted faster than the non hydroxylated analogs a certification of this hydroxyl group is possible without loss of potency of the drug the sar

Alterations of the alcohol to an ester and polishes the hydrogen bond donor and is more likely to reduce the h bond acceptor activity of the alcohol oxygen the a made nitrogen at position 1 of the b ring nor its substituents the methyl group are required for binding to the benzodiazepine receptor however if the amine is reduced to a nitrile the affinity of the

Benzodiazepine receptor decreases in vivo activity of the drug is given back by oxidation from the nitrile to the amine temazepam has a high alpha 1 alpha 3 beta 3 and gamma 2 affinity with moderate alpha 2 affinity at the gaba a receptor benzodiazepines are shown to have a high affinity and specifically for binding in the alpha gamma interface it has showed the

Highest affinity at the alpha-1 subunit with its binding mediating the following on target side effects sedation amnesia untaek sia and anti convulsive and reinforcing behavior temazepam is used to treat insomnia by causing sedation in elderly patients ataxia which is uncontrolled muscle movement is a very common side effect patients on temazepam are subject to

Change in their mood expressing a more aggressive behavior take care to counsel patients if they are experiencing the aggressive behavior or worsening symptoms of insomnia it’s affinity at the alpha 2 & 3 subunit causes the on target side effects of muscle relaxation and anzala says the development of physical dependence results from the affinity at the gaba 2

Subunit this issue can arise from use for longer than 2 to 4 weeks the off target side effects of temazepam include gi disturbances hypertension urinary retention and incontinence the reduced dose of temazepam for an alternative form of hypnotic drug should be considered in those patients who are experiencing these severe side effects thank you for listening and

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Transcribed from video
Group 3 DDMDA Video Project- Temazepam By Emin Tahir